Endocarditis Associated Glomerulonephritis

Endocarditis associated glomerulonephritis is an immune complex glomerulonephritis complicating infective endocarditis, caused by deposition of bacterial antigen with antibody and complement within the glomerulus. Glomerulonephritis occurs in about 20 to 30% of patients with infective endocarditis at autopsy, but is clinically evident in fewer than 10%.

In the past the commonest organism was viridans streptococcus on a native valve; today Staphylococcus aureus predominates, particularly in acute disease, injecting drug use and healthcare related infection, with a rising frequency in older adults with degenerative valve disease and in men. Right sided staphylococcal endocarditis in people who inject drugs is a particularly frequent setting.

Pathophysiology. Bacterial antigen in the circulation forms immune complexes that deposit in the mesangium and subendothelial space and activate complement, producing endocapillary proliferation (diffuse proliferative or membranoproliferative pattern) and, in some cases, crescents. Kidney injury in endocarditis has other contributors: septic emboli with infarction, antibiotic related interstitial nephritis, vancomycin or aminoglycoside toxicity, haemodynamic injury and contrast.

• Endocarditis: fever, new or changing murmur, splenomegaly, anaemia, weight loss, back pain, night sweats.
• Peripheral stigmata: Osler nodes, Janeway lesions, splinter haemorrhages, Roth spots, petechiae.
• Kidney: haematuria (microscopic in most), proteinuria (usually under 3 g daily; nephrotic range occasionally), hypertension, oedema, acute kidney injury, rapidly progressive glomerulonephritis with crescents in a minority.
• Embolic phenomena: stroke, infarction of spleen, kidney or limbs; flank pain with haematuria suggests renal infarction.
• Low C3 in 60 to 90% (C4 usually normal or modestly low); rheumatoid factor positive in about half; ANCA (usually PR3) is positive in a proportion of cases and may mimic vasculitis.

Red flags

• Fever with new heart failure, conduction block on ECG (PR prolongation suggests root abscess) or a new regurgitant murmur.
• Rising creatinine with crescents, or oliguria.
• Vegetation larger than 10 mm, embolic events, or persistent bacteraemia beyond 5 to 7 days of appropriate treatment.
• Positive ANCA in a febrile patient with a heart murmur: do not start immunosuppression until endocarditis is excluded.
• Prosthetic valve, intracardiac device or injecting drug use.

• At least 3 sets of blood cultures from separate venepuncture sites over 24 hours (ideally before antibiotics); extend incubation if organisms are slow growing; repeat cultures every 24 to 48 hours until negative.
• Echocardiography: transthoracic first, transoesophageal when transthoracic is negative with high suspicion, in prosthetic valves, or for complications (abscess, perforation); repeat after 5 to 7 days if the first study is negative and suspicion remains. CT or PET of the whole body for emboli and device infection where needed.
• Creatinine, urea, electrolytes, urine microscopy (dysmorphic red cells, red cell casts), urine protein:creatinine ratio, C3, C4, rheumatoid factor, ANCA, cryoglobulins, hepatitis B and C, HIV.
• Kidney biopsy only when the diagnosis is unclear or function declines despite effective antibiotics: diffuse endocapillary proliferation with neutrophils, subendothelial and mesangial deposits (IgG, IgM, C3); crescents in a minority; staphylococcal disease may show IgA-dominant deposits.

Differential diagnosis

• Acute interstitial nephritis from antibiotics, vancomycin or aminoglycoside acute tubular injury, renal infarction from emboli, ANCA associated glomerulonephritis, post-infectious glomerulonephritis from another site, IgA vasculitis, cryoglobulinaemic glomerulonephritis, thrombotic microangiopathy, infected shunt or device with immune complex disease.

First line: eradicate the infection (the glomerulonephritis usually resolves with it)

• Empirical therapy until cultures return (acute presentation):
  • Vancomycin loading dose 25 to 30 mg/kg intravenously, then adjusted to trough 15 to 20 mg/L (or area under the curve 400 to 600) with levels before every dose in kidney impairment
  • Plus gentamicin only if the benefit clearly exceeds the risk (avoid in kidney impairment when alternatives exist)
  • Add rifampicin 300 to 600 mg twice daily for prosthetic material once blood cultures are negative
• Methicillin susceptible Staphylococcus aureus, native valve: flucloxacillin 2 g intravenously every 4 hours (maximum 12 g daily; reduce frequency when eGFR is under 10) for 4 to 6 weeks; cefazolin 2 g every 8 hours is an alternative (adjust dose to eGFR).
• Methicillin resistant Staphylococcus aureus: vancomycin loading dose 25 to 30 mg/kg then adjusted to trough 15 to 20 mg/L, or daptomycin 8 to 10 mg/kg intravenously once daily (every 48 hours when eGFR is under 30), for 6 weeks.
• Viridans and other penicillin susceptible streptococci: benzylpenicillin 1.2 g intravenously every 4 hours (or amoxicillin 2 g every 4 hours) for 4 weeks; ceftriaxone 2 g once daily for 4 weeks is a no adjustment alternative; extend to 6 weeks for prosthetic valves.
• Enterococci: amoxicillin 2 g every 4 hours with ceftriaxone 2 g every 12 hours for 6 weeks (avoids aminoglycoside).
• Prosthetic valve: 6 weeks of combined therapy with specialist input; consider early surgery.
• Dose all antibiotics to current eGFR; recheck levels, creatinine and urine daily during the first week.

Surgery (decide jointly with cardiology and cardiac surgery within days)

• Heart failure from valve dysfunction, uncontrolled infection (abscess, persistent bacteraemia after 5 to 7 days of effective therapy, resistant organisms), vegetation above 10 mm with embolic events, or fungal endocarditis.
• Kidney failure alone is not a contraindication; perioperative acute kidney injury risk is high.

Treatment of the glomerulonephritis

• Antibiotics alone usually produce recovery within weeks; complement normalises in 4 to 8 weeks.
• Immunosuppression is generally avoided while infection is active. In crescentic disease with deteriorating function despite 1 to 2 weeks of effective antibiotics, discuss specialist led methylprednisolone 500 mg intravenously daily for 3 days, then prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) tapered rapidly. Plasma exchange is reserved for severe ANCA-positive crescentic disease.
• Supportive: blood pressure below 130/80 mmHg once stable; ramipril only after infection is controlled and potassium is stable; sodium under 2 g daily; furosemide 40 to 80 mg for fluid overload.
• Avoid NSAIDs, iodinated contrast and aminoglycosides where possible. Stop anticoagulants unless a mechanical valve requires them (risk of haemorrhagic stroke).

Kidney replacement therapy. Indications: potassium above 6.5 mmol/L refractory to treatment, pH under 7.15, fluid overload unresponsive to diuretics, uraemic complications. Haemodialysis catheters must be placed after bacteraemia is controlled where possible. About 10 to 20% of patients need temporary dialysis; most recover.

Monitoring. Blood cultures until negative twice, temperature, C-reactive protein twice weekly, creatinine daily then twice weekly, C3 at 2 and 6 weeks, echocardiography at completion, urine protein:creatinine ratio at 3 months. Dental review and source control before discharge; antibiotic prophylaxis before dental procedures in high risk patients (prosthetic valve, previous endocarditis).

Referral and escalation. Urgent cardiology, cardiac surgery, infectious diseases and nephrology together from diagnosis; intensive care for shock, heart failure or neurological events.

Special groups

• Injecting drug use: add addiction treatment from the start; outpatient parenteral therapy only with a safe plan.
• Older adults: higher rates of aminoglycoside and vancomycin injury; use levels.
• Dialysis patients: haemodialysis catheter infection with endocarditis; remove the line and delay a new line until cultures are clear.
• Children: congenital heart disease is the main risk; weight based antibiotics with specialist input.