Infection Associated Interstitial Nephritis

Infection associated interstitial nephritis is inflammation of the kidney interstitium caused by systemic infection. It arises either from direct infection of the kidney (pyelonephritis, tuberculosis, BK virus) or from a reactive immune response to organisms in other organs.

Organisms causing the reactive form include leptospirosis, hantavirus, streptococci, Legionella, rickettsia, cytomegalovirus, Epstein-Barr virus, brucellosis, malaria and HIV.

It accounts for about 5 to 10% of acute interstitial nephritis in high income settings and a larger share in tropical regions. There, leptospirosis, hantavirus (haemorrhagic fever with renal syndrome), malaria, scrub typhus and tuberculosis are major contributors.

The lesion is an interstitial lymphocytic and plasma cell infiltrate with tubular injury. The clinical presentation is acute kidney injury with sterile or infected pyuria, often with systemic features of the infection.

Pathophysiology. Direct tubular invasion, deposition of microbial antigens with a local T-cell response, systemic cytokine release, and in some cases haemodynamic injury or rhabdomyolysis contribute. Persistent infection may cause granulomatous disease (tuberculosis) or chronic fibrosis.

• Fever, myalgia, headache and rash with acute kidney injury; oliguria occurs in some, while non-oliguric injury with hypokalaemia is typical of leptospirosis.
• Leptospirosis: conjunctival suffusion, calf tenderness, jaundice, haemorrhage, pulmonary haemorrhage, hypokalaemia from distal tubular potassium wasting; after exposure to water, rodents or livestock.
• Hantavirus: fever, thrombocytopenia, hypotension, oliguria followed by polyuria, from rodent exposure.
• Tuberculosis: sterile pyuria, haematuria, flank pain, ureteric strictures, with constitutional symptoms; renal failure in advanced disease.
• BK virus nephropathy: rising creatinine in a kidney transplant recipient 2 to 12 months after transplant, with decoy cells in urine.
• HIV: tubulointerstitial nephritis and diffuse infiltrative lymphocytosis syndrome.
• Other: Legionella (pneumonia with kidney injury), brucellosis, Mycoplasma, Epstein-Barr virus.

Red flags

• Jaundice with acute kidney injury and haemorrhage (Weil disease).
• Pulmonary haemorrhage, shock or encephalopathy.
• Oliguria or anuria with potassium above 6.0 mmol/L.
• Transplant recipient with rising creatinine and BK viraemia.
• Haematuria and pyuria with negative cultures (tuberculosis).

• History: travel, animal, water and occupational exposure, immune status, transplantation.
• Full blood count, platelets, C-reactive protein, liver tests, creatine kinase, creatinine, potassium, urinalysis (sterile pyuria, white cell casts), urine protein:creatinine ratio, urine and blood cultures.
• Leptospirosis: PCR on blood (first 7 to 10 days) and urine (after the first week), microscopic agglutination test or IgM serology on paired samples.
• Hantavirus: PCR and IgM serology.
• Tuberculosis: three early morning urine samples for acid fast bacilli and culture, urine nucleic acid amplification, chest radiograph, CT urogram (calyceal irregularity, strictures, calcification).
• BK virus: plasma and urine PCR (plasma above 10 000 copies/mL suggests nephropathy), urine decoy cells; transplant biopsy with viral inclusions and SV40 staining.
• HIV, cytomegalovirus, Epstein-Barr virus, Legionella urinary antigen, brucella serology and culture, malaria film and rapid antigen test where relevant.
• Kidney biopsy when the cause is unclear or function fails to improve: interstitial infiltrate, tubulitis, granulomas (tuberculosis, sarcoid), viral inclusions.

Differential diagnosis

• Drug induced interstitial nephritis from antibiotics given for the infection, sepsis associated acute tubular injury, pyelonephritis, glomerulonephritis, rhabdomyolysis, sarcoidosis, IgG4 related disease, tubulointerstitial nephritis with uveitis.

First line: treat the infection and support the kidney

• Leptospirosis:
  • Mild disease: doxycycline 100 mg orally twice daily for 7 days.
  • Severe disease: benzylpenicillin 1.2 g (2 million units) intravenously every 6 hours for 7 days (reduce for eGFR under 10) or ceftriaxone 1 g intravenously daily for 7 days.
  • Start without waiting for confirmation.
  • Early dialysis (daily haemodialysis or high volume peritoneal dialysis) for oliguria or hyperkalaemia; replace potassium for hypokalaemia; intensive care for pulmonary haemorrhage.
• Hantavirus: supportive care; avoid nephrotoxins. Renal replacement therapy is needed in about 20% (potassium above 6.5 mmol/L refractory, pH under 7.15, overload). Ribavirin has limited evidence and is not routinely used.
• Renal tuberculosis:
  • Isoniazid 300 mg, rifampicin 600 mg (450 mg when weight is under 50 kg), pyrazinamide 25 mg/kg and ethambutol 15 mg/kg daily for 2 months, then isoniazid and rifampicin for 4 months (extend to 9 to 12 months when disease is extensive).
  • When eGFR is under 30, give pyrazinamide 25 mg/kg and ethambutol 15 mg/kg three times weekly after dialysis.
  • Pyridoxine 25 mg daily; monitor liver tests.
  • Consider prednisolone 20 to 40 mg daily for 4 to 6 weeks for ureteric strictures; stents or surgery for obstruction.
• BK virus nephropathy: reduce immunosuppression (tacrolimus target trough 3 to 5 ng/mL, mycophenolate mofetil reduced by 50% or stopped, switch to an mTOR inhibitor in selected patients). Monitor BK viraemia every 2 to 4 weeks. Intravenous immunoglobulin 0.2 to 2 g/kg for refractory cases; no approved antiviral.
• Legionella: azithromycin 500 mg daily or levofloxacin 750 mg daily (every 48 hours when eGFR is under 50) for 7 to 14 days.
• Brucellosis: doxycycline 100 mg twice daily with rifampicin 600 to 900 mg daily for 6 weeks.
• HIV: antiretroviral therapy irrespective of CD4 count. Use dolutegravir 50 mg with tenofovir alafenamide 25 mg and emtricitabine 200 mg daily when eGFR is at least 30; avoid tenofovir disoproxil with reduced eGFR.
• Malaria: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours, then daily (no dose reduction for kidney injury). Follow with oral artemether and lumefantrine (4 tablets at 0, 8, 24, 36, 48 and 60 hours for adults over 35 kg).
• Dose all antimicrobials to the current eGFR; avoid aminoglycosides, vancomycin and NSAIDs where alternatives exist.

Corticosteroids. Not routine. Do not give steroids while infection is uncontrolled. Consider prednisolone 1 mg/kg daily (maximum 60 mg) for 1 to 2 weeks, tapered over 4 to 6 weeks, when all of the following apply:

• biopsy shows significant interstitial inflammation
• infection is controlled
• function fails to recover after 1 to 2 weeks

Supportive care. Manage fluid status; avoid contrast. Correct hyperkalaemia:

• calcium gluconate 10% 10 mL intravenously over 10 minutes
• insulin 10 units with glucose 25 g
• salbutamol 10 to 20 mg nebulised
• sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily

Give sodium bicarbonate 500 mg to 1 g two to three times daily for bicarbonate under 22 mmol/L.

Kidney replacement therapy. Indications: potassium above 6.5 mmol/L refractory to treatment, pH under 7.15, fluid overload unresponsive to diuretics, uraemic pericarditis or encephalopathy. Early start in leptospirosis and hantavirus reduces mortality.

Monitoring. Creatinine, potassium and urine output daily in acute injury; leptospiral PCR or titres at follow up; BK viral load every 2 to 4 weeks; creatinine and urine protein:creatinine ratio at 3 and 12 months.

Referral and escalation. Nephrology and infectious diseases together; intensive care for shock, pulmonary haemorrhage or severe jaundice; transplant team for BK virus nephropathy.

Special groups

• Transplant recipients: BK virus, cytomegalovirus and adenovirus; reduce immunosuppression under the supervision of the transplant centre.
• Pregnancy: leptospirosis and malaria are high risk; penicillin or ceftriaxone for leptospirosis; avoid doxycycline.
• Sub-Saharan Africa: consider tuberculosis, HIV, malaria, leptospirosis and schistosomiasis in every case of tubulointerstitial disease.