Sjögren Associated Tubulointerstitial Nephritis

Sjögren associated tubulointerstitial nephritis is the commonest kidney lesion in primary Sjögren syndrome, an autoimmune exocrinopathy in which lymphocytes infiltrate salivary, lacrimal and other epithelial tissue. Sjögren syndrome affects about 0.5 to 1% of adults, with a female to male ratio of 9 to 1, and kidney disease may be the presenting feature.

Kidney involvement is clinically evident in 5 to 10% of patients (up to 30% with sensitive testing for tubular acidification defects). It is most often a chronic tubulointerstitial nephritis with lymphocytic and plasma cell infiltrates that mainly damages the distal tubule and collecting duct.

Consequences include:

• Distal (type 1) renal tubular acidosis
• Hypokalaemia
• Nephrogenic diabetes insipidus
• In a few patients, proximal tubulopathy (Fanconi syndrome)
• Progressive chronic kidney disease (about 10% reach eGFR under 60)

A less common glomerular form (membranoproliferative or cryoglobulinaemic glomerulonephritis, membranous nephropathy) occurs in 1 to 3%. It usually comes with cryoglobulins, low C4 and higher lymphoma risk.

Pathophysiology. Autoreactive T cells and B cells infiltrate the tubulointerstitium and damage the distal tubular acid secreting alpha intercalated cells (loss of H-ATPase and chloride bicarbonate exchanger), with later interstitial fibrosis.

• Sicca symptoms: dry eyes and mouth, dental caries, parotid enlargement, vaginal dryness.
• Tubular: polyuria, polydipsia, muscle weakness or paralysis from hypokalaemia (potassium under 2.5 mmol/L), metabolic acidosis, nephrocalcinosis and stones, bone pain and osteomalacia, growth delay (children).
• Kidney function: mildly or moderately reduced eGFR, bland sediment, low grade proteinuria (under 1 g daily), sterile pyuria.
• Extraglandular: arthralgia, Raynaud phenomenon, purpura, neuropathy, interstitial lung disease, thyroid disease.
• Lymphoma (5 to 10% lifetime): persistent parotid swelling, lymphadenopathy, splenomegaly, low C4, cryoglobulins, monoclonal protein.

Red flags

• Potassium under 2.5 mmol/L with weakness, arrhythmia or periodic paralysis.
• Severe acidosis (bicarbonate under 15 mmol/L).
• Low C4, cryoglobulins, purpura or monoclonal protein (lymphoma, glomerulonephritis).
• Rapid decline in eGFR or proteinuria above 1 g daily (glomerular disease).
• Pregnancy with anti-Ro antibodies.

• Creatinine, eGFR, electrolytes (potassium, chloride, bicarbonate), venous or arterial blood gas, calcium, phosphate, magnesium, urine pH on a fresh sample (persistently above 5.5 with systemic acidosis suggests distal acidosis), urine anion gap (positive), urine calcium and citrate, urine osmolality, urine protein:creatinine ratio.
• Acidification test when pH is equivocal: furosemide 40 mg with fludrocortisone 1 mg orally (urine pH under 5.3 is normal), or ammonium chloride loading with caution.
• Anti-Ro (SSA) and anti-La (SSB), antinuclear antibodies, rheumatoid factor, immunoglobulins (raised IgG), C3, C4, cryoglobulins, serum protein electrophoresis and free light chains.
• Schirmer test, ocular staining, salivary flow, minor salivary gland biopsy (focus score at least 1 focus in 4 mm²).
• Kidney ultrasound (nephrocalcinosis); kidney biopsy for unexplained decline: dense interstitial lymphocytic and plasma cell infiltrate with tubulitis and fibrosis; immunostaining for IgG4 to exclude IgG4 related disease.
• Lymphoma screen where indicated.

Differential diagnosis

• Other causes of distal renal tubular acidosis (medication such as amphotericin and lithium, genetic, medullary sponge kidney, hypercalciuria), systemic lupus erythematosus, sarcoidosis, IgG4 related disease, drug induced interstitial nephritis, hypokalaemic periodic paralysis, cryoglobulinaemic glomerulonephritis.

Correct acidosis and potassium (symptomatic therapy is essential)

• Alkali: sodium bicarbonate 500 mg to 1 g two to three times daily, or potassium citrate 30 to 60 mEq daily in divided doses. Both correct acidosis and hypokalaemia and reduce stones. Titrate to bicarbonate at least 22 mmol/L (in distal acidosis up to 1 to 2 mmol/kg daily may be needed). Recheck bicarbonate and potassium at 1 to 2 weeks.
• Severe hypokalaemia (under 2.5 mmol/L) or ECG changes: intravenous potassium chloride 10 to 20 mmol each hour. The maximum is 20 mmol each hour with ECG monitoring through a central line, and 10 mmol each hour peripherally. Correct acidosis only after potassium. Recheck potassium at 4 to 6 hours.
• Milder hypokalaemia: oral potassium chloride 40 to 120 mmol daily in divided doses (sustained release tablets). Never give bicarbonate alone before replacing potassium.
• Nephrocalcinosis and stones: fluids above 2.5 litres daily, potassium citrate, sodium under 2 g daily, avoid calcium supplements.
• Osteomalacia: cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily. Give phosphate replacement if low, and calcium 500 mg elemental calcium daily with meals.

Immunosuppression (for progressive loss of function, extraglandular disease or active inflammation)

• Prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for 4 to 8 weeks, then taper over 6 to 12 months to 5 mg daily. Start early for eGFR under 60 or falling. Response is best when fibrosis is limited; tubular acidosis may persist.
• Rituximab 1 g on days 1 and 15 (or 375 mg/m² weekly for 4 doses), repeated every 6 months when effective. It is especially useful for cryoglobulinaemia, glomerulonephritis or lymphoproliferative disease.
• Steroid sparing: azathioprine 1 to 2 mg/kg daily, mycophenolate mofetil 1 g twice daily, or methotrexate 7.5 to 15 mg weekly (avoid with eGFR under 30).
• Hydroxychloroquine 200 to 400 mg daily (maximum 5 mg/kg) for fatigue, arthralgia and rash; yearly eye review.
• Prophylaxis: co-trimoxazole 480 mg daily and proton pump inhibitor during high dose prednisolone. Screen for hepatitis B before rituximab.

Sicca symptoms. Artificial tears, pilocarpine 5 mg three times daily (reduce when eGFR is under 30) or cevimeline 30 mg three times daily; dental care.

Chronic kidney disease. Target blood pressure below 130/80 mmHg. Give ramipril 2.5 mg daily increased to 10 mg daily, and stop if potassium exceeds 6.0 mmol/L (check potassium carefully because alkali treatments lower it). Avoid NSAIDs and nephrotoxins. Dialysis is indicated at eGFR 5 to 10 with symptoms; transplantation is possible.

Monitoring.

• Bicarbonate, potassium, creatinine and urine protein:creatinine ratio every 2 to 4 weeks until stable, then every 3 months
• Yearly lymphoma surveillance (examination, blood count, C4, protein electrophoresis)
• Bone density and urinary calcium yearly

Referral and escalation. Rheumatology and nephrology together; haematology for lymphoma or monoclonal protein; urgent for severe hypokalaemia, acidosis or rapid loss of function.

Special groups

• Pregnancy: anti-Ro antibodies carry a 2% risk of congenital heart block. Arrange foetal echocardiography at 16 to 26 weeks; hydroxychloroquine 200 to 400 mg daily lowers recurrence. Continue alkali and potassium replacement. Avoid ACE inhibitors, methotrexate and mycophenolate.
• Children: growth failure and rickets; early alkali therapy.
• Older adults: monitor for lymphoma and bone disease.