Lupus nephritis

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

Lupus nephritis results from immune-complex deposition and complement-driven inflammation across glomerular, tubulointerstitial and vascular compartments. Because SLE activity fluctuates, a normal creatinine does not rule out important nephritis and extrarenal symptoms may be quiet. Screening is proactive and repeated. Once abnormalities emerge, biopsy provides the treatment map and distinguishes potentially reversible inflammation from chronic scar.

Histological class is necessary but not sufficient. Focal class III and diffuse class IV proliferative lesions can cause rapidly progressive injury; class V membranous disease produces a proteinuric or nephrotic phenotype; mixed III or IV plus V is common. Activity indices, crescents and necrosis indicate inflammatory burden, while global sclerosis and interstitial fibrosis predict limited reversibility. Antiphospholipid vasculopathy or thrombotic microangiopathy may require anticoagulation, haematology or complement-focused decisions rather than simply more lupus immunosuppression.

The treatment landscape has moved towards early combination therapy. The 2026 BSR guideline recommends combined renal–rheumatology services and, for new or relapsing class III/IV disease, glucocorticoid and hydroxychloroquine with a mycophenolic-acid analogue plus obinutuzumab, voclosporin or tacrolimus, or belimumab. Availability, licensing, kidney function, nephrotic phenotype, extra-renal activity, infection, reproductive plans and patient preference determine choice. Cyclophosphamide-based treatment remains a specialist alternative in selected severe disease or when other regimens are unsuitable.

Key points

Lupus nephritis may be clinically silent, so every SLE review includes blood pressure, urinalysis, serum creatinine and quantitative proteinuria rather than waiting for oedema.
New proteinuria, glomerular haematuria, casts or unexplained kidney dysfunction should trigger urgent combined renal and rheumatology review and timely kidney biopsy.
Anti-dsDNA rise and C3 or C4 fall support immunological activity but neither proves a renal flare, excludes infection nor replaces urine and biopsy assessment.
The ISN/RPS classes describe mesangial, proliferative, membranous and sclerosing patterns; class, activity, chronicity and coexisting vascular or interstitial lesions all alter treatment.
Class III or IV proliferative nephritis, with or without class V, needs prompt induction; class VI reflects advanced sclerosis where immunosuppression cannot restore scarred glomeruli.
Current 2026 BSR guidance favours glucocorticoid and hydroxychloroquine with a mycophenolic-acid analogue plus obinutuzumab, a calcineurin inhibitor or belimumab for new or relapsing proliferative disease.
Reduced glucocorticoid exposure and a planned taper are preferred when response and histological risk permit because cumulative steroid toxicity drives long-term damage.
Hydroxychloroquine is background therapy for most people unless contraindicated, with dose adjustment and retinal screening informed by body weight and kidney function.
Proteinuria may improve slowly and calcineurin inhibitors can lower it through podocyte effects; assess eGFR, sediment, serology and adherence before calling early non-response.
Mycophenolate, cyclophosphamide, ACE inhibitors, ARBs and several newer agents are unsuitable in pregnancy; pre-conception switching must be planned while disease is quiet.
Antiphospholipid-associated thrombosis, thrombotic microangiopathy, infection and medicine toxicity can worsen kidneys alongside immune-complex nephritis and require distinct treatment.
Long-term kidney protection includes blood-pressure and proteinuria control, vaccination, cardiovascular-risk care, avoidance of nephrotoxins and sustained specialist follow-up after remission.

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

Systemic lupus immune-complex disease

Loss of immune tolerance in SLE generates nuclear autoantibodies and circulating or locally formed immune complexes that target susceptible renal compartments.

Renal vascular lupus overlap

Antiphospholipid antibodies, thrombotic microangiopathy and severe hypertension can add vascular kidney injury alongside glomerular immune-complex nephritis and require distinct assessment.

Relapsing inflammatory activity

Fluctuating systemic autoimmunity, treatment interruption or inadequate disease control can permit new renal activity, while infection may mimic or precipitate clinical deterioration.

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

1
Autoantibody and complex formation
Antinuclear antibodies bind released cellular antigens, forming immune complexes that circulate or assemble within renal tissue.
2
Complement-driven inflammation
Deposits activate complement and recruit inflammatory cells across mesangial, subendothelial or subepithelial sites, producing distinct biopsy classes.
3
Proliferative or membranous injury
Proliferative class III or IV lesions can cause rapidly progressive injury, while class V disease more often produces proteinuric or nephrotic disease.
4
Activity becomes chronicity
Repeated inflammatory episodes replace potentially reversible lesions with glomerulosclerosis, tubular atrophy and interstitial fibrosis, limiting later treatment response.

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

Silent screening abnormality

A new rise in urine ACR or PCR, microscopic haematuria or cellular casts may reveal nephritis before symptoms, oedema or creatinine change.

Proliferative nephritic flareRed flag

Hypertension, glomerular blood, casts, rising creatinine and falling complement suggest active class III or IV disease and require urgent biopsy-led care.

Membranous nephrotic phenotype

Heavy proteinuria, hypoalbuminaemia and oedema with relatively bland sediment may indicate class V disease and carries thrombosis and infection complications.

Infection masquerading as flare

Fever, cytopenia, CRP rise, urinary symptoms, cough or haemodynamic change during immunosuppression requires cultures and source assessment before automatic escalation.

Thrombotic vascular injuryRed flag

Abrupt renal decline, severe hypertension, thrombocytopenia, haemolysis or thrombosis raises antiphospholipid nephropathy or thrombotic microangiopathy and needs urgent multidisciplinary assessment.

Pregnancy-associated uncertainty

Rising pressure, proteinuria or creatinine in pregnancy may be lupus activity, pre-eclampsia or both; complement trend, sediment and maternal–fetal assessment guide interpretation.

Chronic damage phenotype

Long-standing reduced eGFR, small kidneys and a bland sediment may reflect scarring rather than active nephritis, changing the benefit–harm balance of immunosuppression.

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
Detect glomerular inflammation and quantify albumin and total protein loss.
Interpretation and limitations
Red-cell casts support activity, but sediment may be bland in class V; use consistent quantitative samples to judge trajectory.
02
Creatinine, electrolytes and serial eGFR
Why
Identify AKI and distinguish acute trajectory from established CKD.
Interpretation and limitations
A small absolute creatinine rise may be important in a young person with low baseline; interpret calcineurin-inhibitor haemodynamic effects separately from immune response.
03
C3, C4 and anti-dsDNA
Why
Track immunological activity alongside clinical renal measures.
Interpretation and limitations
A fall in complement and rise in dsDNA support flare but are imperfect; stable serology does not exclude nephritis and abnormal serology alone does not mandate escalation.
04
Full blood count, CRP and liver profile
Why
Assess cytopenia, infection, haemolysis clues and treatment safety.
Interpretation and limitations
Disproportionately high CRP can suggest infection, while thrombocytopenia plus haemolysis redirects urgently towards thrombotic microangiopathy.
05
Antiphospholipid antibodies and haemolysis tests
Why
Evaluate vascular thrombosis, pregnancy risk and microangiopathic renal injury where indicated.
Interpretation and limitations
Persistent antiphospholipid positivity requires repeat confirmation in the correct context; anticoagulation can interfere with lupus-anticoagulant testing.
06
Infection screening
Why
Find bacterial, viral and opportunistic infection and establish immunosuppression baselines.
Interpretation and limitations
Obtain cultures and hepatitis, tuberculosis or other regimen-directed tests without unnecessarily delaying organ-saving treatment.
07
Kidney biopsy
Why
Determine ISN/RPS class, activity, chronicity and vascular and tubulointerstitial lesions.
Interpretation and limitations
Biopsy findings guide intensity and likely reversibility; consider repeat biopsy when relapse or non-response could reflect a class change or accumulated scar.
08
Pregnancy and reproductive assessment
Why
Identify pregnancy before teratogenic therapy and plan safe conception, contraception and fertility preservation.
Interpretation and limitations
Mycophenolate and cyclophosphamide require strict safeguards; assess anti-Ro, anti-La and antiphospholipid antibodies during pre-conception planning.

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

Infection-related glomerulonephritis

Fever, positive cultures or a deep source can cause immune-complex nephritis during immunosuppression; infection assessment is essential before calling every serological change a flare.

Antiphospholipid nephropathy or TMA

Abrupt severe hypertension, thrombocytopenia, haemolysis or thrombosis suggests vascular occlusion rather than isolated immune-complex activity, though both may coexist.

Medicine toxicity or haemodynamic AKI

Calcineurin inhibitors, NSAIDs, volume loss and sepsis can raise creatinine with a relatively bland sediment, requiring exposure and perfusion review.

Pre-eclampsia

New hypertension and proteinuria in pregnancy may represent placental disease, lupus activity or both; urine sediment, complement trend and maternal–fetal assessment guide interpretation.

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

01New renal abnormalityScreen, exclude mimics and biopsyFirst stepA person with SLE develops proteinuria, glomerular haematuria, casts, hypertension or unexplained renal dysfunction.

1Quantify proteinuria, inspect sediment, trend creatinine and pressure, and assess fluid state, extra-renal activity, infection, medicines and thrombosis.
2Send complement, dsDNA, blood count, CRP and cause-directed infection and antiphospholipid tests, treating sepsis and acute renal complications immediately.
3Refer urgently to the combined renal–rheumatology service and arrange timely biopsy when safe; do not infer histological class from protein amount alone.

02Proliferative inductionUse contemporary combination therapyBiopsy shows new or relapsing class III or IV nephritis, with or without class V, requiring induction.

1Give specialist intravenous glucocorticoid pulses when indicated, then follow a pre-planned KDIGO oral taper matched to histological severity, response and toxicity risk.
2Continue hydroxychloroquine unless contraindicated and select a mycophenolic-acid analogue combined with obinutuzumab, belimumab or an appropriate calcineurin inhibitor under current BSR and NHS access.
3If combination options are unsuitable or high-risk features demand another route, consider cyclophosphamide or other expert therapy with infection, fertility and cumulative-toxicity safeguards.

03Apparent non-responseFind the reason before escalatingEscalationProteinuria or kidney dysfunction fails to improve along the expected treatment trajectory.

1Verify adherence, medicine exposure, dose, interactions, infection and blood-pressure control and distinguish a calcineurin haemodynamic change from progressive inflammation.
2Reassess urine sediment, eGFR, protein trend, complement and dsDNA and look for thrombosis, thrombotic microangiopathy and another renal disease.
3Discuss repeat biopsy when activity versus chronicity or class transition is uncertain, then switch or intensify treatment according to the revised clinicopathological picture.

04Pregnancy planningAchieve quiet disease on compatible therapyA person with current or previous lupus nephritis wishes to conceive or has pregnancy potential during treatment.

1Plan conception jointly after a sustained period of renal stability, documenting creatinine, proteinuria, blood pressure, antibodies and previous obstetric or thrombotic history.
2Replace mycophenolate, cyclophosphamide, ACE inhibitor, ARB and other incompatible drugs early enough to prove stability on pregnancy-compatible alternatives such as selected azathioprine or tacrolimus regimens.
3Provide maternal-medicine surveillance for pre-eclampsia, renal flare, thrombosis and fetal growth and coordinate hydroxychloroquine and aspirin or anticoagulation decisions with specialists.

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

Background therapy reduces lupus activity and flares and accompanies most lupus-nephritis regimens unless contraindicated.

Hydroxychloroquine

Use a weight- and renal-function-adjusted once-daily dose within the specialist SLE and ophthalmology plan.

Retinal toxicity risk rises with cumulative exposure and kidney impairment; arrange national screening, check interactions and investigate visual or cardiac toxicity symptoms.

Provides the core antiproliferative component of several first-line combination regimens for class III or IV nephritis.

Mycophenolic-acid analogue

Induction and maintenance doses follow the combined renal–rheumatology protocol and are titrated for tolerance and response.

Major teratogenicity, infection, cytopenia and gastrointestinal toxicity require contraception, pregnancy exclusion, blood counts and pre-conception substitution.

B-lymphocyte-stimulator inhibition improves renal response and reduces renal events in selected active proliferative nephritis.

Belimumab

Use the licensed intravenous or subcutaneous specialist regimen alongside mycophenolic-acid therapy and glucocorticoid.

Assess infection, vaccination, mood and hypersensitivity; access and suitability depend on current NHS criteria and the whole extra-renal phenotype.

Combined with mycophenolic-acid therapy, it suppresses immunity and stabilises podocytes, particularly useful in proteinuric disease with adequate renal function.

Calcineurin inhibitor

Voclosporin uses its licensed regimen; tacrolimus is trough-guided under the specialist renal protocol.

Hypertension, hyperkalaemia, neurotoxicity, interactions and a haemodynamic eGFR fall require close monitoring; proteinuria reduction may not equal histological remission.

Provides an alternative potent induction route for selected severe proliferative disease or when preferred combinations are unsuitable.

Cyclophosphamide

Use a specialist intravenous pulse regimen selected for severity, kidney function, age and previous cumulative exposure.

Infection, marrow suppression, infertility, teratogenicity, bladder toxicity and later malignancy require prophylaxis, fertility preservation and exposure tracking.

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

Rapid or chronic kidney failure

Active proliferative lesions may sharply reduce filtration, while repeated flares and chronic scarring progressively reduce renal reserve and treatment reversibility.

Nephrotic complications

Membranous or mixed disease can cause severe hypoalbuminaemia, oedema, venous thrombosis and infection risk through sustained glomerular protein loss.

Hypertension and cardiovascular injury

Sodium retention, vascular lesions and chronic kidney disease promote difficult hypertension, accelerating cardiac, cerebrovascular and further renal damage.

Adverse pregnancy outcomes

Active nephritis, proteinuria, hypertension and reduced kidney function increase maternal deterioration, pre-eclampsia, fetal growth restriction and preterm birth risk.

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

During active nephritis review at least every one to three months and more often when severe, including blood pressure, urinalysis, quantitative protein and renal function.
Trend anti-dsDNA, C3 and C4 with clinical measures but never intensify therapy solely for serological activity in an otherwise stable person.
Follow full blood count, liver profile, immunoglobulins, drug levels and infection screening according to each component of combination immunosuppression.
Judge renal response from proteinuria, eGFR and sediment over an appropriate interval, recognising that chronic protein leak may lag behind control of inflammatory activity.
Maintain hydroxychloroquine retinal screening and review daily dose when weight or kidney function changes.
At every stage revisit vaccination, cardiovascular and bone risk, contraception, pregnancy plans, adherence burden and psychosocial effects of chronic multi-drug treatment.

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

Creatinine is a late screen

Young adults can lose substantial filtration before serum creatinine crosses the laboratory range, so urine protein and sediment are indispensable at routine SLE reviews.

Class can change

A later flare may not reproduce the original biopsy pattern; repeat tissue can distinguish proliferative conversion, membranous disease and irreversible chronic damage.

Proteinuria has two meanings

It can reflect active immune injury or persistent structural and podocyte damage, so a calcineurin-driven fall does not by itself prove immune-complex clearance.

Complement trends are personal

Some patients have chronically low complement and others flare without a dramatic fall; compare with the person's established serological and clinical baseline.

Vascular lesions need separate thinking

Antiphospholipid nephropathy or thrombotic microangiopathy may coexist with immune-complex nephritis and require anticoagulation, plasma therapy or another targeted plan.

Quiet disease precedes conception

Changing teratogenic therapy immediately after pregnancy begins is less safe than planned substitution and demonstrated renal stability before conception.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for creatinine to rise before screening urine and blood pressure in established SLE.
02
Assigning lupus-nephritis class from proteinuria or serology without a timely kidney biopsy.
03
Treating fever and complement change as flare without cultures and focused infection assessment.
04
Equating a rapid calcineurin-inhibitor proteinuria fall with complete control of renal inflammation.
05
Continuing mycophenolate into an unplanned pregnancy or stopping it abruptly without urgent specialist substitution.
06
Escalating immunosuppression for fixed class VI sclerosis where activity and reversibility are absent.