A 76-Year-Old Woman with Rash and Rapidly Progressive Kidney Failure
Purpura, deteriorating kidney function, a stroke, and a new murmur. Walk through the differential with the case team — one piece of evidence at a time.
May 18, 2026 · 18 min · Dr. Sree Hari Reddy MD
1. The Presentation
A 76-year-old retired administrator presents with a 4-week history of fatigue and a recurrent, painless purpuric rash on the lower legs, accompanied by arthralgias and ankle oedema. Her medical history is notable for HCV infection eradicated with sofosbuvir 15 years ago, with sustained virologic cure.
Beyond a thorough history and examination, which initial bedside or laboratory test gives you the highest information yield in the next hour?
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Reasonable later if pulmonary haemorrhage is suspected (haemoptysis, hypoxia), but neither is present. Imaging is not the highest-yield first step here.
✓ Correct
Palpable purpura with any constitutional features (fatigue, arthralgia, oedema) should be treated as small-vessel vasculitis until proven otherwise. The single most prognostic variable in any vasculitis is renal involvement — and urinalysis is the fastest, cheapest screen for glomerular disease. A bland sediment is reassuring; an active sediment changes everything you do next.
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Would address oedema if you suspected DVT, but does not address the more concerning systemic picture suggested by purpura + arthralgia + fatigue.
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Not the highest-yield first investigation. Would only be informative later if an occult malignancy is being hunted.
2. The First Result
Urinalysis shows 3+ blood with >180 RBC per high-power field, and 3+ protein. A 24-hour urine collection quantifies 4.4 g of protein. Her serum creatinine is 2.6 mg/dL; her baseline three months ago was 0.8 mg/dL. She has become oliguric.
Which clinical syndrome best describes this picture?
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AIN typically shows sterile pyuria, urinary eosinophils, and a comparatively bland sediment — not heavy proteinuria with >180 RBC/HPF. This picture is glomerular, not tubulointerstitial.
✓ Correct
An active glomerular sediment (haematuria + heavy proteinuria) plus a rapidly rising creatinine plus an extrarenal vasculitic feature (the palpable purpura) is the textbook syndrome of RPGN from systemic small-vessel vasculitis. The next question is which small-vessel vasculitis — and that branches by the immunology to come.
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There is heavy proteinuria, but the active sediment (haematuria with dysmorphic-range RBC counts) and the rapid creatinine rise are nephritic features. Pure nephrotic syndromes do not produce these.
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Pre-renal AKI gives a bland sediment and minimal proteinuria, not the active nephritic urine seen here.
3. Anchoring the Differential
Small-vessel vasculitis with RPGN partitions on kidney biopsy into three immunofluorescence patterns:
Linear — anti-glomerular basement membrane (anti-GBM) disease.
Immune-complex — IgA vasculitis, cryoglobulinaemic vasculitis, lupus nephritis, post-infectious GN.
Before any complement or antibody data are back — based on epidemiology alone — which mechanism is statistically most likely in a 76-year-old with RPGN and palpable purpura?
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Anti-GBM is rare (~1 per million per year), typically presents as pulmonary–renal syndrome, and does not cause cutaneous vasculitis — it targets only the glomerular and alveolar basement membranes.
✓ Correct
In published series, roughly 80% of patients over 60 presenting with RPGN have ANCA-associated vasculitis. Age + cutaneous vasculitis + RPGN puts AAV at the top of the a priori list — until the serologic data force a re-evaluation. This is the working diagnosis to anchor on for now.
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The immune-complex bucket (IgA vasculitis, cryoglobulinaemia, SLE, post-infectious GN) is a strong second, but each individual diagnosis within it is statistically less likely at age 76 than ANCA-associated vasculitis. Reserve this bucket if/when the data force you out of pauci-immune.
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TMA can cause RPGN, but its hallmark is microangiopathic haemolysis (schistocytes, thrombocytopenia, raised LDH) — none yet documented. Cutaneous vasculitis is also not typical.
4. The Serologies Return
The first wave of immunology comes back: ANA, ANCA (both MPO and PR3), anti-GBM, anti-Ro, anti-La, anti-CCP — all negative. HCV RNA remains undetectable.
How should you reshape the working diagnosis?
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The opposite — a negative ANCA in this clinical context essentially excludes ANCA-associated vasculitis. Pauci-immune disease drops off the differential.
✓ Correct
Negative ANCA + negative anti-GBM closes both pauci-immune and linear patterns. The clinical picture is too compelling to be nothing, so the working bucket is now immune-complex: IgA vasculitis, cryoglobulinaemic vasculitis, lupus nephritis, or post-infectious GN. Complement levels will narrow it further.
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Not at all — biopsy-proven leukocytoclastic vasculitis + active glomerular sediment in the same patient is too compelling. Some vasculitides are seronegative, and the immune-complex group depends on biopsy + complement for diagnosis, not on a specific autoantibody.
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The urine phenotype (heavy proteinuria + active glomerular sediment) is wrong for AIN, regardless of serology. AIN was ruled out two steps ago.
5. Reading the Complement
Serum complement levels return:
C3 41 mg/dL (low; reference 81–157)
C4 less than 6 mg/dL (undetectable; reference 12–39)
A mildly low C3 with a disproportionately low C4 indicates predominant activation of which complement pathway?
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Alternative-pathway activation produces a disproportionate C3 drop with C4 typically preserved — the opposite pattern. Seen in post-infectious GN and C3 glomerulopathy.
✓ Correct
The classical pathway consumes C1, C4, then C2 and C3 in sequence — so when both C3 and C4 are low but C4 is disproportionately depressed, the classical pathway is dominant. In a patient with vasculitis + RPGN, this points to two diagnoses: cryoglobulinaemic vasculitis or SLE. ANA is already negative in this patient, which essentially excludes lupus.
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C3 and C4 are both low, so complement is being consumed. (For reference: AAV and anti-GBM disease classically have normal systemic complement — which is part of why the hypocomplementemia rules them out.)
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Hereditary C4 deficiency would not explain RPGN with active vasculitis; it predisposes to lupus-like disease and infections. The question here is about the consumption pattern in a clearly inflammatory illness.
6. Which Cryoglobulin?
The working diagnosis is now cryoglobulinaemic vasculitis. Cryoglobulins are immunoglobulins that precipitate from serum below 37 °C and redissolve on rewarming. They come in three flavours:
Type I — a single monoclonal Ig (often IgM or IgG).
Type II — mixed: monoclonal IgM (usually kappa) + polyclonal IgG.
Type III — entirely polyclonal IgM + IgG.
Which clinical feature points away from type I cryoglobulinaemia and toward mixed (type II or III)?
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These are features of type I cryoglobulinaemia, which causes injury by mechanical precipitation and small-vessel obstruction in the cold — not by complement-mediated vasculitis.
✓ Correct
Overt vasculitis is the signature of mixed cryoglobulinaemia. The monoclonal IgM in type II has rheumatoid-factor activity — it complexes with polyclonal IgG, and these immune complexes activate the classical complement pathway, producing systemic vasculitis. Type I cryoglobulins (single monoclonal Ig with no RF activity) do not activate complement to anywhere near the same degree.
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This is the definition of type I cryoglobulinaemia.
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Mixed cryoglobulins have RF activity (the monoclonal IgM is the rheumatoid factor). A normal RF would argue against type II/III, not for it.
SPEP: small IgM kappa monoclonal component, 0.12 g/dL
IgG 78 mg/dL (low), IgA 109 (normal), IgM 466 (high)
Free kappa light chain 356 mg/L; kappa:lambda ratio 19.69
Which cryoglobulin type best fits this serologic profile?
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Type I would show a single monoclonal spike without a polyclonal background, and would not have RF activity. The IgM kappa spike alone might suggest this, but the elevated RF + immune-complex GN argue for a mixed component.
✓ Correct
All the boxes are ticked: monoclonal IgM kappa on SPEP, elevated RF (the IgM-anti-IgG activity), and a polyclonal IgG component (admittedly suppressed here by both clonal disease and urinary loss — but still polyclonal). The disproportionate C4 consumption is the classical-pathway fingerprint of type II.
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Type III lacks any monoclonal component. The clear IgM kappa M-spike on SPEP rules this out.
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A cryoglobulin assay would confirm the type, but the serology here is already strongly characteristic — RF positivity + monoclonal IgM + polyclonal background. The cryoprecipitate would refine, not redirect.
8. Hunting the Clone
Type II cryoglobulinaemia is, by its definition, driven by a clonal B-cell process — something has to produce the monoclonal IgM kappa. Historically, chronic HCV infection was the dominant driver worldwide; HCV E2 protein stimulates B-cell expansion via direct binding. This patient’s HCV is eradicated and HCV RNA remains undetectable.
In a patient with type II cryoglobulinaemic vasculitis and no active HCV, the most likely underlying clonal driver is:
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Multiple myeloma produces IgG or IgA monoclonal components in >90% of cases — IgM myeloma is exceedingly rare. The clinical pattern (cryoglobulinaemic vasculitis + immune-complex GN) is also atypical; myeloma kidney is more often cast nephropathy.
✓ Correct
In the largest published series of type II cryoglobulinaemia without active HCV, 91% had a detectable B-cell clonal process, and approximately one third met criteria for an overt lymphoproliferative disorder — most commonly marginal-zone lymphoma or lymphoplasmacytic lymphoma (Waldenström macroglobulinaemia). The remainder fit “monoclonal gammopathy of renal significance”. The next investigation is a bone-marrow biopsy.
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Sjögren’s can drive type II cryoglobulinaemia and can itself evolve into lymphoplasmacytic lymphoma. However, this patient has no sicca features and anti-Ro and anti-La are negative — these essentially exclude Sjögren’s.
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A true idiopathic case is the minority — most are explainable with adequate work-up. Calling this idiopathic without sending bone marrow and looking for an MGRS clone would be premature.
9. Two Findings That Change Plans
You are about to proceed with bone-marrow biopsy and pulse glucocorticoids. The team re-examines the patient and adds two findings:
A new blowing holosystolic murmur at the left sternal border.
Two weeks earlier she had transient word-finding difficulty; an outpatient MRI showed a small subacute infarct in the left posterior insula.
Which condition must be actively excluded before initiating high-dose immunosuppression?
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Amyloidosis is on the differential for a cardiac murmur + multisystem disease, but it is not an acute contraindication to immunosuppression, and it is not the typical mimic of vasculitis.
✓ Correct
IE is the textbook mimic of systemic vasculitis — it produces cutaneous vasculitis, immune-complex glomerulonephritis, polyclonal rheumatoid factor positivity, and embolic strokes. Murmur + recent stroke + vasculitic features + RF + a positive serologic background must prompt blood cultures and trans-oesophageal echocardiography before any immunosuppression. Starting steroids on a patient with active bacterial endocarditis is catastrophic.
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AF would not produce the cardiac murmur (it produces an irregular rhythm) and is not a contraindication to immunosuppression per se, though stroke risk would change.
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Dissection presents acutely with chest or back pain and haemodynamic instability — not a smouldering 4-week illness.
10. The Cultures Speak
Two of four blood culture bottles grow methicillin-sensitive Staphylococcus aureus. Trans-oesophageal echocardiogram shows no vegetation. Review of the timeline pinpoints the likely source as the temporary haemodialysis catheter placed three days earlier.
What is the right next step?
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Tempting given the rapidly progressive kidney disease, but starting immunosuppression with active S. aureus bacteraemia of any source can convert a survivable infection into a fatal one. Defer briefly.
✓ Correct
This is the practical compromise. The bacteraemia is most consistent with a catheter-related infection (no vegetation on TEE, the catheter has been in for three days). It must be cleared with a tunnelled catheter replacement and a course of cefazolin before plasma exchange and immunosuppression resume. In the real case, this is exactly what happened.
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Rituximab is immunosuppressive. B-cell depletion impairs humoral immunity, increases infection risk, and is contraindicated during active bacteraemia.
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No pulmonary findings, no rationale.
11. The Renal Biopsy
After bacteraemia clears, a kidney biopsy is performed. It shows a membranoproliferative pattern with diffuse endocapillary hypercellularity, intracapillary pseudothrombi (PAS-positive, fibrin-negative), and immunofluorescence dominated by IgM (3+) and kappa (3+) along the glomerular basement membranes and in capillary lumens. Electron microscopy reveals deposits with a tubular, curvilinear substructure.
Which biopsy feature is the most specific for cryoglobulinaemic glomerulonephritis?
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MPGN is a light-microscopic pattern, not a diagnosis. It is shared by many immune-complex glomerulopathies (cryoglobulinaemia, HBV/HCV-associated GN, lupus, MGRS, C3 glomerulopathy). It raises suspicion but is not specific.
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Eosinophilic intracapillary plugs that are PAS-positive but fibrin-negative are suggestive of cryoglobulinaemia, but they can occasionally be seen in other immune-complex glomerulopathies with very heavy deposits. Suggestive — not pathognomonic.
✓ Correct
Organised paracrystalline (tubular, curvilinear, or annular) substructure of immune deposits on EM reflects the geometrically ordered arrangement of cryoglobulin immune complexes. It is the closest thing to a “fingerprint” for cryoglobulinaemic glomerulonephritis on biopsy. When you see it with MPGN + pseudothrombi, the diagnosis is essentially clinched.
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C3 is present in virtually every immune-complex GN — it confirms complement activation but does not distinguish cryoglobulinaemia from other entities in the bucket.
12. The Bone Marrow
Bone-marrow biopsy reveals lymphoid aggregates of B cells (CD20+, IgM+, kappa-predominant) with plasmacytic differentiation. Flow cytometry confirms a clonal B-cell population. Genetic testing for the MYD88 L265P mutation — present in over 90% of Waldenström macroglobulinaemia — is NEGATIVE (MYD88-wild-type).
What is the integrated final diagnosis?
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The clone is IgM (not IgG/A), with plasmacytic differentiation arising from a B-cell aggregate — that is lymphoplasmacytic lymphoma, not myeloma. The biopsy also shows cryoglobulinaemic GN, not cast nephropathy.
✓ Correct
Waldenström macroglobulinaemia is lymphoplasmacytic lymphoma with an IgM paraprotein. MYD88-wild-type Waldenström accounts for <10% of cases and is associated with a more aggressive course and poorer response to BTK inhibitors — both important for the treatment plan that follows.
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HCV was eradicated 15 years ago and HCV RNA is undetectable. However, an important footnote: the patient’s original B-cell clone may well have been initiated by HCV decades ago and persisted despite virologic cure — so HCV is part of the back-story, not the active driver.
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The clone has been demonstrated histologically and by flow cytometry. By definition, this is no longer idiopathic.
13. Choosing Therapy
The patient now requires clone-directed therapy. She remains dialysis-dependent. She has MYD88-wild-type disease. The three commonly used first-line regimens for Waldenström macroglobulinaemia are:
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BTK inhibitors are effective in MYD88-mutated Waldenström but show markedly reduced activity in MYD88-wild-type disease. Choosing a BTK inhibitor here is the wrong fit.
✓ Correct
Proteasome-inhibitor-based regimens are the right choice for this patient because (i) none of the drugs requires renal dose adjustment — important given her dialysis-dependence, and (ii) efficacy is independent of MYD88 status. In the real case, this was the chosen initial regimen.
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Bendamustine is highly effective but is given in combination with rituximab, not alone. Bendamustine + rituximab is also a reasonable first-line — but historically it has been deferred when renal function is severely impaired, although emerging data make it increasingly acceptable.
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Not first-line therapy; reserved for selected refractory cases, and inappropriate in a 76-year-old who is dialysis-dependent.
14. An Unexpected Complication
Days after the first dose of rituximab, the patient’s IgM rises acutely with worsening cryoglobulinaemic manifestations — purpura intensifies and renal function deteriorates further.
What is this phenomenon called?
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TLS causes hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia from rapid lysis of malignant cells. It is uncommon in low-tumour-burden indolent lymphomas like Waldenström, and a rising IgM is not its signature.
✓ Correct
A well-described early complication of rituximab in Waldenström: IgM levels rise sharply in the first weeks, transiently worsening hyperviscosity or cryoglobulinaemic disease before B-cell depletion takes hold. Management: plasma exchange for life-threatening manifestations, and combine rituximab with a proteasome inhibitor or alkylator (e.g., bendamustine) that directly suppresses IgM production. Critical point: do not abandon rituximab on the strength of an early IgM rise — it is expected, not a failure.
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Misleading. Calling this treatment failure and switching agents prematurely deprives the patient of effective therapy. The flare is transient.
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Rituximab infusion reactions are cytokine-release reactions occurring during infusion — fever, chills, hypotension, bronchospasm — not a sustained IgM rise over days.
15. Outcome and Take-Aways
What happened next. Plasma exchange was used to control the IgM flare, and therapy was transitioned to bendamustine + rituximab. IgM fell by more than 90%, cryoglobulinaemia went into remission, and dialysis was discontinued two weeks after hospital discharge.
Five months later, however, the patient was diagnosed with metastatic Merkel-cell carcinoma. Despite ongoing haematologic remission of her Waldenström macroglobulinaemia, the carcinoma progressed and she was transitioned to hospice care, where she died peacefully at home several weeks later. Patients with the kind of B-cell dysregulation that drives cryoglobulinaemic vasculitis carry an elevated lifetime risk of a second malignancy — surveillance does not end with haematologic response.
Key learning points
Palpable purpura + any constitutional features = small-vessel vasculitis until proven otherwise. Get a urinalysis in the first hour.
RPGN + cutaneous vasculitis points to systemic small-vessel vasculitis; the next branch is by immunofluorescence pattern — linear (anti-GBM), pauci-immune (ANCA), or immune-complex.
In a patient over 60 with RPGN, ANCA-associated vasculitis is statistically most likely. But pre-test probability must always be re-weighted by new data — here, the negative ANCA and the complement profile rotated the differential within hours.
The complement pattern is diagnostic. ANCA and anti-GBM consume no systemic complement. Disproportionate C4 consumption = classical-pathway disease (cryoglobulinaemia or SLE). Disproportionate C3 consumption = alternative-pathway disease (post-infectious GN, C3 glomerulopathy).
Type II cryoglobulinaemia without active HCV → look hard for a B-cell clone. Up to 91% have a detectable clonal process; one third have overt lymphoma — most commonly marginal-zone lymphoma or Waldenström macroglobulinaemia.
Always exclude infective endocarditis in a patient with cutaneous vasculitis + glomerulonephritis + cardiac murmur or recent stroke. Blood cultures + TEE are non-negotiable before immunosuppression.
MYD88 status changes the treatment plan. Wild-type Waldenström (<10%) is more aggressive and responds less well to BTK inhibitors — proteasome-inhibitor or alkylator-based regimens are preferred.
A rituximab-associated IgM flare is expected, not a failure of therapy. Anticipate it, manage with plasma exchange, and combine rituximab with an alkylator or proteasome inhibitor to suppress IgM production directly.
The most specific biopsy feature for cryoglobulinaemic GN is the tubular / curvilinear substructure on EM — supported by MPGN pattern and intracapillary pseudothrombi on light microscopy.
Patients with B-cell dysregulation carry an elevated lifetime risk of a second malignancy. Surveillance continues even after haematologic remission.