Glomerulonephritis — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Ms Sarah Williams, 32 years old, office manager. ^[1]

Presenting complaint: Three-week history of increasing facial and leg swelling, frothy urine, and joint pains. She has noticed increasing fatigue and a malar rash that worsens with sun exposure. She was seen by her GP two days ago with a blood pressure of 150/95 and proteinuria on dipstick. ^[1]

Past history:

• Systemic lupus erythematosus, diagnosed 3 years ago (positive ANA, anti-dsDNA; arthritis, malar rash, oral ulcers). Currently on hydroxychloroquine 400 mg daily.
• Menorrhagia with iron deficiency anaemia (on oral iron).
• No pregnancies. Sexually active, using the oral contraceptive pill.
• Family history: mother with autoimmune thyroid disease. ^[1]

Current medications:

• Hydroxychloroquine 400 mg daily
• Combined oral contraceptive pill
• Ferrous sulphate 325 mg daily ^[1]

Examination findings (trainee elicits):

• Alert, oriented, Cushingoid nil, temp 37.2, RR 18, HR 82 regular, BP 152/96, SpO2 98% on room air
• Malar rash across the cheeks and bridge of nose, sparing the nasolabial folds
• Two painless oral ulcers on the hard palate
• Thin, sparse hair at the temples (lupus alopecia)
• Cardiovascular: normal heart sounds, no pericardial rub, JVP not elevated
• Respiratory: reduced air entry at both bases, dullness to percussion consistent with bilateral pleural effusions
• Abdomen: soft, non-tender, no organomegaly, no ascites
• Neurological: intact, no mononeuritis
• Skin: erythema nodosum-like nodules on the shins, no palpable purpura
• Musculoskeletal: mild synovitis of the metacarpophalangeal joints bilaterally
• Oedema: bilateral pitting peripheral oedema to mid-calf, periorbital oedema ^[1]

Investigations:

• Creatinine 138 micromol/L (baseline 75 one year ago), eGFR 45 (baseline 80)
• Hb 102 (MCV 78 — microcytic, consistent with iron deficiency), WCC 3.2 (leucopenia), platelets 180
• C3 0.52 g/L (low, normal 0.9 to 1.8), C4 0.07 g/L (low, normal 0.15 to 0.55)
• ANA positive 1:1280, anti-dsDNA positive (strongly), anti-Smith positive
• ANCA negative, anti-GBM negative
• Hepatitis B and C negative, HIV negative
• Urine protein-to-creatinine ratio 340 mg/mmol (proteinuria approximately 3.4 g/day — nephrotic range)
• Urinalysis: blood 2+, protein 4+
• Urine microscopy: dysmorphic RBC, no RBC casts identified
• 24-hour urine or spot PCR confirms nephrotic-range proteinuria
• Renal biopsy: ISN/RPS class IV lupus nephritis — diffuse proliferative GN with active lesions (karyorrhexis, wire loops, cellular crescents in 20% of glomeruli), "full house" immunofluorescence (IgG, IgA, IgM, C3, C1q all positive), subendothelial and mesangial deposits on EM
• Chest X-ray: bilateral pleural effusions
• Echocardiogram: normal systolic function, no pericardial effusion ^[1]

Candidate's structured presentation (model)

Opening statement: ^[1]

"Ms Sarah Williams is a 32-year-old woman with known systemic lupus erythematosus, diagnosed three years ago on hydroxychloroquine, who presents with a three-week history of nephrotic-range proteinuria, oedema, hypertension, and active lupus serology. Her creatinine has risen from a baseline of 75 to 138, and her renal biopsy confirms ISN/RPS class IV lupus nephritis — diffuse proliferative disease with active lesions and cellular crescents in 20% of glomeruli. ^[1]

Her main problems are:

1. Lupus nephritis class IV (diffuse proliferative) with nephritic-nephrotic features — active and requires urgent induction
2. Nephrotic syndrome — proteinuria 3.4 g/day, oedema, and pleural effusions
3. Active extrarenal lupus — malar rash, oral ulcers, arthritis, leucopenia, alopecia
4. Hypertension (BP 152/96)
5. Iron deficiency anaemia from menorrhagia
6. Reproductive health — young woman of childbearing age, implications for immunosuppression and future pregnancy" ^[1]

Investigation summary: ^[1]

"Her serology is classic for active lupus nephritis. The low C3 and low C4 indicate classical complement pathway activation from immune complex deposition. The strongly positive anti-dsDNA with low complement confirms active disease and provides a marker for monitoring treatment response. Her ANCA and anti-GBM are negative, excluding overlap with ANCA-associated or anti-GBM disease. The renal biopsy is the key diagnostic test: class IV lupus nephritis is the most common severe class and carries the worst prognosis if untreated. The presence of crescents in 20% of glomeruli indicates active, severe inflammation but is still potentially reversible with urgent induction. The 'full house' immunofluorescence pattern is pathognomonic for lupus nephritis." ^[1]

Management plan: ^[1]

1. Urgent induction immunosuppression:

   • Corticosteroids: Methylprednisolone 500 to 1000 mg IV daily for 3 days, followed by oral prednisone 0.5 to 1 mg/kg/day (approximately 30 to 40 mg), tapering rapidly per the PEXIVAS reduced-dose strategy ^[2].
   • Immunosuppressive agent: Mycophenolate mofetil, starting at 500 mg BD and titrating to target 2 to 3 g/day (1 g BD to 1.5 g BD) over 2 to 4 weeks, for 6 months of induction. Alternatively, the Euro-Lupus cyclophosphamide regimen (500 mg IV every 2 weeks for 6 doses) — either is acceptable first-line per KDIGO 2021. Given her wish to preserve fertility and the equivalence data, MMF is the preferred choice for this young woman. ^[1]

2. Continue hydroxychloroquine 400 mg daily — this reduces lupus flares, including renal flares, and improves long-term outcomes. It is safe in pregnancy and should be continued. ^[1]

3. Management of nephrotic syndrome:

   • RAAS blockade: Start an ACE inhibitor (e.g., ramipril 2.5 mg OD, titrated) to reduce proteinuria and control blood pressure. Target blood pressure below 130/80. Monitor creatinine and potassium closely.
   • Diuretics: Furosemide 40 mg OD for oedema and pleural effusions, titrated to clinical response.
   • Venous thromboembolism prophylaxis: Nephrotic-range proteinuria confers a high VTE risk (loss of antithrombin III in the urine). Prophylactic anticoagulation should be considered, particularly with serum albumin below 25 g/L. I would check serum albumin and discuss with haematology. ^[1]

4. Supportive care:

   • PJP prophylaxis: Trimethoprim-sulfamethoxazole 800/160 mg three times weekly for the duration of high-dose corticosteroid therapy.
   • Bone protection: Calcium and vitamin D supplementation, DEXA scan to guide bisphosphonate use.
   • Gastric protection: Proton pump inhibitor during high-dose corticosteroid therapy.
   • Iron supplementation: Continue for iron deficiency; consider IV iron if oral is poorly tolerated or ineffective. ^[1]

5. Reproductive health:

   • Counselling: Both mycophenolate mofetil and cyclophosphamide are teratogenic and contraindicated in pregnancy. She must use reliable contraception throughout induction and maintenance with MMF. She is already on the oral contraceptive pill — I would review this is appropriate and ensure she understands the importance.
   • Future pregnancy planning: If she wishes to conceive, MMF must be stopped and switched to azathioprine (which is safe in pregnancy) at least 3 months before conception. Hydroxychloroquine and low-dose prednisone (below 10 mg) are safe in pregnancy. Lupus nephritis should be in remission for at least 6 months before conception to minimise the risk of flare and pre-eclampsia. ^[1]

6. Monitoring:

   • Weekly review for the first month: blood pressure, creatinine, proteinuria, FBC (for MMF cytopenia and leucopenia), electrolytes, and disease activity markers (C3, C4, anti-dsDNA).
   • Monthly review thereafter: clinical assessment, proteinuria trend (PCR or ACR), renal function, complement, and immunosuppression toxicity monitoring.
   • Target response: reduction in proteinuria by 25% at 3 months and 50% at 6 months; stabilisation or improvement in creatinine; normalisation of complement. ^[1]

Examiner discussion questions

Q: "You chose mycophenolate over cyclophosphamide for induction. Justify that." ^[1]

"Both are first-line per KDIGO 2021. The ALMS induction trial ^[3] showed MMF is equivalent to IV cyclophosphamide for induction — it was not superior, but it was noninferior, with a different and generally more favourable toxicity profile. For Ms Williams specifically, MMF is preferred for three reasons: first, she is a young woman of childbearing age, and cyclophosphamide causes ovarian toxicity and infertility — the Euro-Lupus low-dose regimen reduces this risk, but MMF avoids it entirely. Second, MMF has less alopecia, nausea, and cytopenia than cyclophosphamide. Third, she can be maintained on MMF after induction, avoiding a drug switch. ^[1]

The one situation where I would reconsider is if she had very severe disease (creatinine rapidly rising, crescents in over 50% of glomeruli, or rapidly deteriorating) — in that setting, some nephrologists prefer cyclophosphamide for its more rapid onset. With 20% crescents and a creatinine of 138, MMF is appropriate." ^[1]

Q: "What is the role of rituximab in her treatment?" ^[1]

"Rituximab is not first-line induction for lupus nephritis — the LUNAR trial ^[4] did not meet its primary endpoint when rituximab was added to MMF and steroids for induction. However, rituximab has a role in refractory disease (failure to respond to MMF or cyclophosphamide after 6 months), in patients who cannot tolerate MMF, and as maintenance in relapsing disease. For Ms Williams, I would reserve rituximab for second-line if she fails MMF induction." ^[1]

Q: "Her complement is low. How will you use it to monitor her response?" ^[1]

"In lupus nephritis, complement levels and anti-dsDNA titres are markers of disease activity. As her lupus nephritis responds to treatment, I expect C3 and C4 to normalise and anti-dsDNA to fall. I monitor these monthly during induction and then every 3 to 6 months during maintenance. A falling complement with a rising anti-dsDNA during follow-up may herald a renal flare and warrants expedited review with repeat urinalysis and proteinuria measurement. However, complement and dsDNA are imperfect — some patients flare with normal serology, and I always treat the patient, not the numbers." ^[1]

Q: "She wants to become pregnant in two years. How does that affect your plan?" ^[1]

"This is a critical question. Lupus nephritis and pregnancy interact in several ways. First, lupus nephritis must be in remission for at least 6 months before conception to minimise the risk of renal flare, pre-eclampsia, and fetal loss. Second, certain drugs must be stopped before conception — mycophenolate mofetil is teratogenic and must be switched to azathioprine at least 3 months before. Cyclophosphamide is also teratogenic and causes infertility. Third, hydroxychloroquine is safe and should be continued throughout pregnancy — it reduces flares. Fourth, low-dose prednisone (below 10 mg) is safe; high-dose steroids and rituximab are avoided in pregnancy where possible. Fifth, aspirin 100 to 150 mg daily should be commenced from early pregnancy to reduce the risk of pre-eclampsia, which is increased in women with lupus nephritis and CKD. ^[1]

For Ms Williams, I would plan her treatment with this timeline: 6 months of MMF induction, then switch to azathioprine maintenance for at least 2 years. If she is in remission at that point (proteinuria below 500 mg/day, stable creatinine, normal complement), I would transition her pregnancy-safe regimen and refer to a maternal-fetal medicine specialist for pre-conception counselling and a planned pregnancy. I would involve her rheumatologist and obstetric physician in this planning from the outset." ^[1]

Q: "What is her long-term renal prognosis?" ^[1]

"Class IV lupus nephritis carries a 10 to 30% risk of ESKD over 10 years despite treatment, depending on the severity at presentation, the response to induction, and the frequency of relapses. Her prognosis is relatively favourable: her creatinine is only mildly elevated (138), her crescent burden is moderate (20%), and she is being treated early. With a good response to induction (proteinuria reduction and complement normalisation) and sustained maintenance, she has a good chance of long-term renal preservation. ^[1]

However, she is at lifelong risk of renal flare, which causes cumulative damage and accelerates progression to ESKD. Each flare adds to the risk of irreversible scarring. This is why maintenance immunosuppression must continue for at least 2 to 3 years, and why close monitoring is essential. I would also optimise her cardiovascular risk (she is at high lifetime cardiovascular risk from lupus, CKD, and chronic inflammation) — smoking cessation (if she smokes), lipid management, blood pressure control, and exercise." ^[1]