Level: Advanced — nephrology trainees and nephrologists
Educational disclaimer: This fictional case is for postgraduate education and does not replace clinical judgment, local protocols, multidisciplinary review, current prescribing information, or individual patient factors.
Learning objectives
After completing this case, learners should be able to recognize high-risk active lupus nephritis (LN), interpret a mixed proliferative and membranous biopsy pattern, distinguish supportive care from disease-directed treatment, and weigh a newly approved B-cell-directed add-on option against its safety, reproductive, and access considerations.
Stage 1 — Presentation and diagnostic framing
A 31-year-old woman with systemic lupus erythematosus (SLE), diagnosed six years earlier, is referred urgently with progressive edema, foamy urine, hypertension, and fatigue. Her SLE history includes photosensitivity, inflammatory arthritis, and immune thrombocytopenia. She has continued hydroxychloroquine but discontinued mycophenolate mofetil (MMF) eighteen months ago after a sustained period of low disease activity. She is not pregnant, would like to consider pregnancy in approximately two years, and agrees to effective contraception while active disease is treated.
During the preceding three weeks, she has gained 4 kg and developed ankle edema, arthralgia, and lower exercise tolerance. Her blood pressure is 166/102 mmHg. Examination identifies 2+ bilateral ankle edema but no fever, murmur, livedo, focal neurological deficit, or active synovitis.
| Investigation | Result |
|---|---|
| Serum creatinine | 1.23 mg/dL; prior 0.68 mg/dL |
| Estimated GFR | 57 mL/min/1.73 m² |
| Urine protein–creatinine ratio (UPCR) | 5.8 g/g |
| Urine microscopy | Dysmorphic red cells and red-cell casts |
| Serum albumin | 2.6 g/dL |
| Complement C3/C4 | Both low |
| Anti-dsDNA antibody | Markedly increased from baseline |
| Hemoglobin / platelets | 9.8 g/dL / 178 × 10⁹/L |
| Pregnancy test and urine culture | Negative |
Decision point 1
Which interpretation is most appropriate?
| Option | Interpretation |
|---|---|
| A | The proteinuria can be observed while renin–angiotensin system blockade is optimized. |
| B | The combination of rising creatinine, active urinary sediment, nephrotic-range proteinuria, hypocomplementemia, and increased anti-dsDNA makes active glomerular inflammation highly likely and warrants urgent kidney biopsy and specialist-led treatment planning. |
| C | The normal platelet count excludes active lupus nephritis. |
| D | The negative urine culture excludes all causes of acute kidney injury, so biopsy is unnecessary. |
Preferred decision: B. This is a high-risk renal presentation. Supportive treatment for blood pressure and edema is necessary, but cannot substitute for establishing the renal lesion and directing immunosuppression. Kidney biopsy remains central to classification and to separating potentially reversible active injury from chronic damage.[1]
Stage 2 — Biopsy, differential refinement, and immediate risks
Kidney biopsy shows ISN/RPS Class IV-G (A) diffuse proliferative LN with a membranous Class V component. The activity index is 13/24 and chronicity index 2/12. Approximately 20% of glomeruli contain cellular crescents. There is no thrombotic microangiopathy (TMA), no anti-GBM pattern, and only mild interstitial fibrosis/tubular atrophy.
The treating team should now address blood pressure, edema, kidney-protective therapy, thrombosis risk in nephrotic syndrome, infection exclusion, adherence, and reproductive counseling in parallel with immunosuppression planning. The low chronicity score and active lesions make the possibility of recovery clinically meaningful, but do not eliminate the risk of irreversible nephron loss if control is delayed.
Decision point 2
Which statement best guides the next step?
| Option | Interpretation |
|---|---|
| A | Cellular crescents automatically require plasma exchange as routine initial treatment for LN. |
| B | The Class V component means that proliferative-LN therapy is no longer relevant. |
| C | The biopsy confirms active mixed proliferative/membranous LN. Plasma exchange is not a routine response to crescents alone; a separate indication, such as a concomitant process, must be demonstrated. |
| D | The absence of TMA makes blood-pressure management and antiphospholipid-antibody assessment unnecessary. |
Preferred decision: C. The biopsy supports prompt combination immunosuppression in addition to supportive management. It also provides important negative findings: if TMA, antiphospholipid-associated nephropathy, or anti-GBM disease is suspected clinically, those diagnoses require separate evaluation and may change the rescue strategy. They should not be presumed from crescents alone.[1]
Stage 3 — Selecting an initial regimen and discussing a newer option
The multidisciplinary team proposes pulse intravenous glucocorticoids followed by a planned oral taper and MMF, while continuing hydroxychloroquine unless contraindicated and implementing kidney-protective care. Because of severe proteinuria, high histologic activity, and the goal of limiting ongoing glucocorticoid exposure, the team discusses obinutuzumab as an add-on to standard therapy.
Obinutuzumab is a type II anti-CD20 B-cell-depleting antibody. In the United States it is FDA-approved for adults with active LN who are receiving standard therapy.[3] It should not be framed as monotherapy or as a universal replacement for MMF, glucocorticoids, belimumab, or voclosporin. The selection of an add-on must be individualized: renal function and proteinuria trajectory, extrarenal disease, prior response, infection history, infusion burden, reproductive plans, access, cost, and patient preferences all matter.[1] [2]
In REGENCY, participants receiving obinutuzumab or placebo also received MMF and a structured glucocorticoid taper. At week 76, complete renal response occurred in 46.4% of participants given obinutuzumab and 33.1% given placebo.[4] The trial supports the option but does not establish superiority over other modern add-on strategies, because direct comparative trials are lacking.
Decision point 3
Which approach best describes an appropriate discussion of obinutuzumab in this case?
| Option | Interpretation |
|---|---|
| A | Use obinutuzumab alone so MMF and glucocorticoids can be stopped immediately. |
| B | Defer all treatment until the patient has finished future pregnancy plans. |
| C | Add obinutuzumab to standard therapy only after infection, hepatitis B, hematologic, vaccination, reproductive, and infusion-risk considerations have been reviewed; incorporate the patient’s values and local access. |
| D | Use the drug only after every other modern therapy has failed, irrespective of disease severity or labeling. |
Preferred decision: C. Current U.S. labeling specifies obinutuzumab for active LN in adults receiving standard therapy. It carries important safety warnings, including hepatitis B reactivation and PML, and requires appropriately supervised intravenous administration.[5]
| Domain | Educational management plan |
|---|---|
| Disease-directed therapy | Use glucocorticoids and MMF as standard therapy, with an add-on chosen by individualized shared decision-making. |
| Obinutuzumab regimen | The U.S. label specifies 1,000 mg intravenously initially, at week 2, week 24, week 26, and then every six months. Premedication and infusion monitoring are required.[5] |
| Infection and vaccine planning | Exclude active infection; complete hepatitis B screening before treatment; review vaccinations and avoid live-virus vaccines during treatment and until B-cell recovery.[5] |
| Kidney protection | Address blood pressure, sodium and edema management, renin–angiotensin system blockade when clinically appropriate, and cardiovascular/thrombotic risk. |
| Reproductive care | Confirm non-pregnancy, provide contraception during active therapy, and revisit a planned conversion to a pregnancy-compatible regimen only after disease control and specialist review. |
Stage 4 — Longitudinal reassessment and possible escalation
At three months, the patient reports better energy and less edema. Her creatinine is 0.95 mg/dL and UPCR is 3.3 g/g. She has not had an infusion reaction, fever, respiratory symptoms, or recurrent urinary infection. Her prednisone dose is being reduced according to the team’s protocol. She asks whether the residual proteinuria means therapy has failed.
Decision point 4
What is the most appropriate response?
| Option | Interpretation |
|---|---|
| A | Declare treatment failure immediately and switch all immunosuppression without further assessment. |
| B | Stop monitoring because the serum creatinine has improved. |
| C | Continue longitudinal assessment of proteinuria, kidney function, urine sediment, blood pressure, treatment tolerance, adherence, infection, and glucocorticoid toxicity; reassess the diagnosis or consider repeat biopsy if the trajectory becomes discordant or unexpectedly worsens. |
| D | Increase glucocorticoids indefinitely until proteinuria is absent. |
Preferred decision: C. Improvement in kidney function and proteinuria is reassuring but not equivalent to complete response. Response assessment is trajectory-based and must include safety and adherence. KDIGO emphasizes structured reassessment of an unsatisfactory response before reflexively escalating therapy.[1]
Expert synthesis
This case illustrates a young adult with severe, active mixed proliferative and membranous LN. The renal biopsy defines the lesion and helps balance urgency against reversibility. A new treatment should be presented as an add-on to standard therapy, never as a substitute for informed clinical judgment, infection screening, kidney-protective measures, reproductive planning, or serial reassessment.
Obinutuzumab is a relevant new U.S. option for adults with active LN receiving standard therapy. Its benefit in REGENCY must be interpreted in the context of the study population and background therapy; there is no direct trial evidence establishing that it is the preferred add-on for every patient. The best choice is therefore individualized and multidisciplinary.
References
[1] [inline_viewer url="https://kdigo.org/wp-content/uploads/2024/01/KDIGO_2024_Lupus_Nephritis_Guideline.pdf"]
[5] [inline_viewer url="https://www.gene.com/download/pdf/gazyva_prescribing.pdf"]
Advanced self-assessment
Complete the 10-question Advanced self-assessment below. Detailed explanations are provided after submission.