Lupus nephritis

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

Lupus nephritis is immune-mediated kidney involvement in SLE and can be silent until screening reveals protein, blood or a creatinine trend. Rheumatology owns the systemic activity, antibody profile, extra-renal disease and immunosuppression strategy jointly with nephrology, while renal clinicians contribute biopsy interpretation, kidney protection, fluid and electrolyte care and replacement planning. Neither specialty should manage a severe case in isolation. A normal creatinine does not reassure when a young person has new proteinuria or active sediment.

Kidney biopsy is the decisive tissue assessment when clinically indicated. The ISN/RPS classes range from mesangial disease through focal or diffuse proliferative nephritis, membranous disease and advanced sclerosis. Treatment decisions require more than the class number: activity index estimates potentially reversible inflammation, chronicity estimates scarring, and vascular or tubulointerstitial lesions may expose APS, TMA or another process. Protein quantity alone cannot reliably distinguish these patterns.

Modern proliferative-nephritis treatment uses planned combination therapy with reduced glucocorticoid exposure. Mycophenolic-acid treatment often forms the antiproliferative backbone, combined according to BSR guidance and access with obinutuzumab, belimumab or a calcineurin inhibitor. Cyclophosphamide remains important for selected severe disease, adherence circumstances or when preferred combinations are unsuitable. Maintenance continues for years after response because premature withdrawal risks relapse; selection considers fertility, pregnancy, infection and previous cumulative exposure.

Non-response is a diagnostic problem before it is a prescribing problem. Missed doses, inadequate exposure, infection, uncontrolled pressure, renal-vein or APS thrombosis, TMA, calcineurin haemodynamics, chronic scarring and a changed histological class can all resemble resistant inflammation. Pregnancy needs pre-conception transition to compatible therapy and a period of proven stability. Long-term follow-up continues after remission and after transplantation because systemic lupus and cardiovascular risk remain.

Key points

Screen every person with SLE using blood pressure, creatinine, urinalysis and quantitative protein when abnormal; absence of oedema or urinary symptoms does not exclude nephritis.
New proteinuria, glomerular blood, casts or unexplained renal decline warrants urgent combined nephrology-rheumatology review and timely kidney biopsy when safe.
Anti-dsDNA rise and C3 or C4 fall can support immunological activity but do not prove a renal flare, determine histological class or exclude infection.
Biopsy reports ISN/RPS class plus activity, chronicity, vascular and tubulointerstitial lesions; the reversible-inflammatory and permanent-scar components guide intensity and prognosis.
When biopsy shows focal or diffuse proliferative nephritis, including a membranous component, begin specialist glucocorticoid-sparing induction without avoidable delay; advanced class VI sclerosis will not recover through escalating immunosuppression.
Current BSR guidance supports hydroxychloroquine plus glucocorticoid and a mycophenolic-acid backbone combined with an appropriate B-cell or calcineurin-directed treatment for many new or relapsing proliferative cases, with cyclophosphamide retained for selected severe or unsuitable cases.
Define response with proteinuria, urine sediment, eGFR, pressure, complement, dsDNA and extra-renal activity over time; protein can fall slowly and must not be interpreted alone.
Before declaring treatment failure, verify adherence and exposure, check infection, thrombosis, TMA, pressure and medicine toxicity, and consider repeat biopsy when activity versus scar remains uncertain.
Maintain kidney protection through pressure and protein control, smoking cessation, cardiovascular prevention, vaccination and avoidance of nephrotoxins alongside immune treatment.
Mycophenolate, cyclophosphamide, ACE inhibitors, ARBs and voclosporin are incompatible or unsuitable in pregnancy; switch before conception while renal disease is stable.

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

Systemic lupus autoimmunity

Loss of tolerance to nuclear material generates circulating and in-situ immune complexes that target susceptible glomerular, vascular and tubulointerstitial compartments.

Host and disease modifiers

Ancestry, genetic complement and immune variants, delayed access to care, hypertension, smoking and previous renal injury influence incidence, severity and long-term outcome.

Vascular and treatment contributors

Antiphospholipid antibodies, thrombotic microangiopathy, medicine nephrotoxicity and infection can damage kidneys alongside or instead of active immune-complex nephritis.

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

1
Immune-complex deposition
DNA-containing immune complexes form or lodge in glomeruli, activate classical complement and recruit inflammatory cells, producing haematuria, protein leak and declining filtration.
2
Histological pattern determines behaviour
Mesangial, proliferative, membranous and globally sclerosed patterns differ in inflammatory activity, proteinuria, reversibility and treatment need; mixed classes are frequent.
3
Activity becomes chronic damage
Endocapillary inflammation, crescents and necrosis may respond to immunosuppression, whereas glomerulosclerosis, interstitial fibrosis and tubular atrophy represent limited reversibility.
4
Proteinuria has several mechanisms
Immune capillary injury, podocyte dysfunction, scarring and systemic pressure raise urinary protein; calcineurin inhibitors can lower protein through podocyte and haemodynamic effects without proving histological remission.

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

Silent screening abnormality

New dipstick protein or blood, rising ACR or PCR, hypertension or a creatinine trend may be the only clinical sign of lupus nephritis.

Proliferative nephritic pattern

Glomerular haematuria, red-cell casts, hypertension and impaired filtration suggest inflammatory proliferative disease, but biopsy establishes class and reversibility.

Membranous nephrotic pattern

Heavy proteinuria, oedema, hypoalbuminaemia and thrombosis risk may occur with class V disease despite a relatively bland sediment.

Pulmonary-renal emergencyRed flag

Haemoptysis, anaemia, hypoxia and diffuse infiltrates with active urine may represent pulmonary haemorrhage and requires immediate multidisciplinary treatment.

Microangiopathic patternRed flag

Severe pressure, platelet fall, schistocytes, haemolysis and neurological or renal injury suggests TMA, requiring an emergency haematology-renal pathway.

Pregnancy overlap

New hypertension and proteinuria after twenty weeks can represent pre-eclampsia, nephritis or both; maternal and fetal assessment must be integrated.

Red flags requiring action

New glomerular haematuria, casts, rising proteinuria or kidney dysfunction in SLE needs urgent combined renal and rheumatology assessment even without oedema.
Haemoptysis with falling haemoglobin and diffuse infiltrates may represent pulmonary-renal disease and requires emergency respiratory and renal support.
Thrombocytopenia, schistocytes, haemolysis and organ injury indicates possible thrombotic microangiopathy, APS or TTP rather than uncomplicated immune-complex nephritis.
Fever, urinary symptoms, hypotension or respiratory infection during induction must be assessed before attributing kidney deterioration to immune flare.
Pregnancy with rising pressure, proteinuria or renal dysfunction requires urgent maternal-medicine assessment because pre-eclampsia and nephritis may overlap.

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
Urinalysis, microscopy, ACR and PCRFirst step
Why
Identify glomerular inflammation and quantify albumin and total protein using repeatable measures.
Interpretation and limitations
Dysmorphic red cells and casts support activity, yet sediment can be bland in membranous disease; confirm contamination and follow quantitative trajectory.
02
Creatinine, electrolytes, eGFR and blood pressure
Why
Detect acute complications, measure filtration trend and establish kidney-protection needs.
Interpretation and limitations
A small creatinine rise is meaningful from a low baseline; interpret potassium, fluid state and calcineurin-related haemodynamic change alongside immune activity.
03
C3, C4 and anti-dsDNA
Why
Follow immunological activity beside direct renal measurements.
Interpretation and limitations
Falling complement and rising anti-dsDNA support flare in some patients but cannot classify nephritis or replace biopsy and infection assessment.
04
FBC, film, reticulocytes, LDH, haptoglobin and CRP
Why
Detect cytopenia, haemolysis, microangiopathy, infection and treatment toxicity.
Interpretation and limitations
Schistocytes and thrombocytopenia redirect urgently toward TMA; CRP is contextual and cannot safely rule infection in or out alone.
05
Kidney biopsy
Why
Define class, activity, chronicity and vascular, interstitial or alternative pathology when the result changes treatment.
Interpretation and limitations
This is the reference tissue assessment for renal phenotype; consider repeat biopsy for unexplained relapse or non-response when class change versus scar matters.
06
Antiphospholipid and infection assessment
Why
Identify coexisting thrombosis, TMA triggers and infections that change immediate management.
Interpretation and limitations
Interpret lupus anticoagulant around anticoagulant interference, obtain cultures before antibiotics when safe, and tailor hepatitis, TB and viral screening to planned therapy.

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

Pre-eclampsia

After twenty weeks of pregnancy, hypertension, proteinuria, liver change, thrombocytopenia and fetal compromise may reflect pre-eclampsia; complement, sediment and broader lupus findings can help but overlap persists.

Antiphospholipid nephropathy or TMA

Severe hypertension, thrombosis, schistocytes, platelet fall and vascular lesions suggest APS-associated nephropathy, TTP or another thrombotic microangiopathy requiring a distinct emergency pathway.

Infection or medicine toxicity

Pyelonephritis, viral infection, interstitial nephritis, NSAIDs, calcineurin inhibitors and haemodynamic medicines can alter urine or filtration during lupus treatment.

Another glomerular disease

IgA nephropathy, diabetic kidney disease, ANCA vasculitis, minimal-change disease and hereditary or paraprotein disorders can coexist and may only be separated by biopsy.

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

01First-line renal detectionQuantify, triage and biopsyFirst stepFirst lineSLE review identifies new protein, glomerular blood, hypertension or declining renal function.

1Repeat a clean urine sample, quantify ACR or PCR, examine sediment, trend creatinine and pressure and assess fluid, thrombosis, infection and extra-renal activity.
2Send complement, anti-dsDNA, blood count, haemolysis and targeted cultures while treating hyperkalaemia, pulmonary oedema, severe hypertension or sepsis immediately.
3Refer urgently to a combined service and arrange kidney biopsy when safe; do not select induction from protein quantity or serology alone.

02Preferred proliferative inductionCombine early and taper steroidsPreferredBiopsy shows active class III or IV nephritis, with or without class V, and meaningful reversibility.

1Give protocolised intravenous methylprednisolone when severity warrants, then a reduced-dose oral taper with predefined response and toxicity review.
2Continue appropriately dosed hydroxychloroquine and use a mycophenolic-acid analogue with the commissioned B-cell or calcineurin-directed partner selected for histology, kidney function and extra-renal disease.
3PreferredAlternativeUse cyclophosphamide or another expert alternative when preferred combinations are unsuitable, with infection prophylaxis, fertility preservation and cumulative-exposure safeguards.

03Apparent non-responseReassess mechanism before switchingProteinuria, active sediment or eGFR fails to improve along the expected trajectory.

1Verify adherence, dose, drug exposure, interactions, blood pressure and time on therapy; review infection and calcineurin haemodynamic effects.
2Evaluate APS thrombosis, TMA, renal-vein thrombosis, another kidney disease and established chronic damage using focused tests and imaging.
3Discuss repeat biopsy when active inflammation versus scar or class transition remains uncertain, then intensify or switch against the revised clinicopathological diagnosis.

04Maintenance and pregnancyProtect remission across life stagesRenal response is achieved or pregnancy is being planned after previous nephritis.

1Continue effective maintenance for the specialist-agreed duration, taper glucocorticoid, control pressure and proteinuria and monitor urine, eGFR, serology and toxicity.
2Before conception replace mycophenolate, cyclophosphamide, voclosporin, ACE inhibitor and ARB with compatible alternatives early enough to prove renal stability.
3During pregnancy coordinate maternal-medicine surveillance for renal flare, pre-eclampsia, thrombosis and fetal growth, with APS and anti-Ro or anti-La plans where relevant.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Antiproliferative backbone for many proliferative and proteinuric lupus-nephritis combinations and a maintenance option after response.

Mycophenolate mofetil

Specialist induction commonly starts at 500 mg orally twice daily and increases as tolerated to 1–1.5 g twice daily; maintenance often uses 500 mg–1 g twice daily according to response, toxicity and the protocol.

Exclude pregnancy and provide effective contraception; mycophenolate is teratogenic and must be changed before conception. Monitor FBC, liver and renal function, infection and gastrointestinal toxicity, and adjust or withhold for serious infection under specialist advice.

Rapidly suppresses glomerular inflammation while slower combination therapy takes effect.

Reduced-dose glucocorticoid induction

For active proliferative disease, specialists may give intravenous methylprednisolone 250–1,000 mg daily for one to three doses, then oral prednisolone no more than about 0.5 mg/kg/day with a protocolised taper toward 5 mg/day by six months when response permits.

Obtain cultures and address infection before or alongside emergency treatment, monitor glucose, pressure, mood, eyes and bone, provide infection and gastric prophylaxis when indicated, and never stop sustained treatment abruptly.

Adds B-cell survival-factor inhibition to selected proliferative-nephritis regimens and may reduce renal events and extra-renal activity.

Belimumab

Use 200 mg subcutaneously once weekly or 10 mg/kg intravenously on days 0, 14 and 28 and then every 28 days, combined with standard specialist lupus-nephritis treatment.

Screen infection and vaccination status and monitor hypersensitivity, injection reactions, mood and suicidality. Confirm NHS eligibility and coordinate reproductive decisions because pregnancy evidence remains less established.

Calcineurin inhibition combined with mycophenolate and glucocorticoid for selected active class III, IV or V nephritis with adequate baseline kidney function.

Voclosporin

The licensed adult dose is 23.7 mg orally twice daily, approximately twelve hours apart, with eGFR and blood pressure checks and protocol-directed interruption or reduction.

Do not start when eGFR is 45 mL/min/1.73 m² or below unless benefits justify risk. Monitor eGFR, hypertension, potassium, QT risk and CYP3A4 interactions; avoid pregnancy and do not equate rapid protein reduction with histological cure.

Potent induction alternative for severe proliferative disease, selected adherence situations or when preferred combinations are unsuitable.

Low-dose intravenous cyclophosphamide

The Euro-Lupus regimen is 500 mg intravenously every two weeks for six doses under a specialist protocol; alternative higher-dose regimens are reserved for selected circumstances.

Provide infection screening and prophylaxis, antiemesis, blood monitoring and bladder protection as indicated. Discuss infertility preservation, teratogenicity, cumulative malignancy risk and previous exposure before treatment.

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

Chronic kidney disease

Repeated inflammatory episodes and delayed response accumulate glomerular and interstitial scar, leading to hypertension, kidney failure, dialysis or transplantation.

Thrombosis and cardiovascular harm

Nephrotic protein loss, APS, hypertension, dyslipidaemia, inflammation and corticosteroid exposure combine to accelerate venous, arterial and cardiovascular events.

Infection and treatment toxicity

Combination immunosuppression can cause serious infection, cytopenia, gonadal injury, malignancy, diabetes, bone loss, ocular toxicity and calcineurin-related hypertension or nephrotoxicity.

Adverse pregnancy outcomes

Active nephritis, CKD, hypertension and antiphospholipid antibodies increase pre-eclampsia, fetal growth restriction, preterm birth, thrombosis and maternal renal deterioration.

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

During induction monitor blood pressure, fluid state, creatinine, eGFR, potassium, urine sediment and quantitative protein frequently enough to detect both response and toxicity.
Trend complement, anti-dsDNA and extra-renal activity as supportive measures, never as substitutes for urine and kidney trajectory.
Apply medicine-specific FBC, liver, infection, immunoglobulin, eGFR, blood-pressure and vaccination schedules and document withheld or restarted doses.
Assess adherence non-judgementally through dosing history, access, adverse effects and where appropriate drug levels before declaring refractory disease.
After response continue long-term urine, pressure, eGFR, cardiovascular, bone and malignancy surveillance because renal relapse and treatment damage remain possible.
Review contraception and pregnancy plans repeatedly, and document the intended transition and washout before any incompatible medicine is stopped.

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

Creatinine can lag

A young adult may lose meaningful filtration before creatinine crosses a laboratory range, making individual baseline and urine findings essential.

Protein is not a biopsy

Heavy protein does not distinguish membranous from mixed proliferative disease, and modest protein can accompany dangerous active inflammation.

Activity and chronicity coexist

A biopsy may contain treatable inflammation and irreversible scar simultaneously, so response expectations and immunosuppression intensity must be realistic.

Calcineurin response needs context

Podocyte stabilisation can lower protein quickly while haemodynamic eGFR change or residual immune activity still requires assessment.

Renal and systemic care are inseparable

An induction choice should address kidney histology while accounting for skin, joints, haematology, neuropsychiatric disease, fertility and infection risk.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for oedema, a large creatinine rise or symptoms before screening urine in SLE.
02
Inferring nephritis class from protein amount, anti-dsDNA or complement and treating without tissue assessment when biopsy is indicated.
03
Calling persistent proteinuria treatment failure without checking adherence, pressure, scar, thrombosis, infection and time course.
04
Escalating immunosuppression for AKI before excluding sepsis, obstruction, medicine haemodynamics and TMA.
05
Using cumulative high-dose oral glucocorticoid without a taper, prevention plan or steroid-sparing combination.
06
Planning pregnancy by abruptly stopping mycophenolate or renin-angiotensin blockade without first establishing a compatible stable regimen.