Sarcoid Tubulointerstitial Nephritis

Sarcoid tubulointerstitial nephritis is non-caseating granulomatous interstitial inflammation of the kidney caused by sarcoidosis, and it is the commonest histological kidney lesion in sarcoidosis. Clinically significant kidney involvement occurs in 1 to 5% of people with sarcoidosis, though granulomas are found at autopsy in 15 to 40%.

Sarcoidosis affects about 1 to 10 in each 10 000 people, most often adults aged 25 to 60 years, with a higher frequency in people of African ancestry and women. Kidney disease can precede, accompany or follow pulmonary and other organ involvement, and may be the only manifestation.

Calcium disorders add to injury: macrophages produce excess calcitriol, causing hypercalciuria, hypercalcaemia, nephrocalcinosis and kidney stones (10 to 20% of patients).

Pathophysiology. Granuloma formation (CD4 T cells, epithelioid macrophages) distorts tubules and interstitium, with subsequent fibrosis. Hypercalcaemia and hypercalciuria cause tubular injury, nephrogenic diabetes insipidus and nephrocalcinosis.

• Raised creatinine with a bland sediment, mild proteinuria (under 1 g daily), sterile pyuria, mild haematuria.
• Tubular dysfunction: low molecular weight proteinuria, distal acidosis, glycosuria, concentrating defect.
• Hypercalcaemia (polyuria, polydipsia, constipation, confusion), hypercalciuria, kidney stones, nephrocalcinosis.
• Systemic sarcoidosis: cough, dyspnoea, hilar lymphadenopathy, erythema nodosum, uveitis, arthralgia, fatigue, lupus pernio, cardiac and neurological involvement.
• Rare: granulomatous renal mass, glomerulonephritis (membranous, IgA, crescentic), renal artery stenosis, obstruction from retroperitoneal nodes.

Red flags

• Creatinine rising over weeks in a patient with sarcoidosis, or kidney injury with hilar nodes.
• Corrected calcium over 3.0 mmol/L or symptoms of hypercalcaemia.
• Cardiac involvement (arrhythmia, heart block) or neurosarcoid.
• Eye symptoms (uveitis).
• Proteinuria over 1 g daily (consider a glomerular lesion).

• Creatinine, eGFR, calcium, phosphate, albumin, alkaline phosphatase, parathyroid hormone (low or suppressed), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (raised), serum angiotensin converting enzyme (insensitive, about 60%), urinary calcium (24-hour), urinalysis, urine protein:creatinine ratio, beta-2 microglobulin.
• Chest radiograph and CT chest (hilar nodes, parenchymal disease); positron emission tomography for occult activity; ECG and cardiac imaging; eye review.
• Kidney biopsy: interstitial non-caseating epithelioid granulomas with giant cells, lymphocytes, plasma cells and fibrosis; negative stains for acid fast bacilli and fungi; exclude other granulomatous causes.
• Exclusion of other causes of granulomatous interstitial nephritis: tuberculosis, fungal infection, drugs (allopurinol, antibiotics, NSAIDs), ANCA vasculitis, IgG4 related disease, Crohn disease, Sjögren syndrome, lymphoma.
• Biopsy of an easier site (lymph node, skin, endobronchial) if kidney biopsy is not possible.

Differential diagnosis

• Tuberculous interstitial nephritis, drug induced interstitial nephritis, IgG4 related disease, granulomatosis with polyangiitis, hypercalcaemia from hyperparathyroidism or malignancy, other causes of nephrocalcinosis, lymphoma.

First line: corticosteroids (start promptly; delay causes fibrosis)

• Prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for 4 to 8 weeks.
• Then taper by 5 to 10 mg every 2 to 4 weeks to 10 mg daily by 3 to 4 months. Continue 5 to 10 mg daily for a total of 12 months or longer.
• Creatinine usually improves in 1 to 3 months, though 40 to 50% have residual loss of function.
• Cover: proton pump inhibitor, and glucose and blood pressure monitoring.
• Calcium 500 mg elemental calcium with meals, only if serum calcium and urinary calcium are normal (avoid supplements in hypercalcaemia).
• Co-trimoxazole 480 mg daily when prednisolone 20 mg or more continues for over 4 weeks (with another immunosuppressant).
• Bone protection with alendronic acid 70 mg weekly when eGFR is at least 35.

Steroid sparing and relapse therapy (for relapse, intolerance or doses over 10 mg daily after 6 months)

• Mycophenolate mofetil 1 g twice daily, or azathioprine 1 to 2 mg/kg daily (check thiopurine methyltransferase activity), or methotrexate 7.5 to 15 mg weekly with folic acid 5 mg weekly (avoid when eGFR is under 30).
• Refractory disease: infliximab 3 to 5 mg/kg intravenously at 0, 2 and 6 weeks, then every 8 weeks (screen for tuberculosis and hepatitis B first), or adalimumab 40 mg subcutaneously every 2 weeks; rituximab 1 g on days 1 and 15 in selected cases.
• Hydroxychloroquine 200 to 400 mg daily (maximum 5 mg/kg actual weight) for skin and mild disease; reduced dose when eGFR is under 30.

Calcium disorders

• Avoid vitamin D supplements, calcium supplements, thiazide and sunlight excess.
• Restrict dietary calcium to 800 to 1000 mg daily when hypercalciuric. Keep fluid intake over 2.5 litres daily.
• Use citrate (potassium citrate 30 to 60 mEq daily in divided doses) for stones with low urine citrate.
• Hypercalcaemia: intravenous 0.9% sodium chloride 1 to 2 litres over 4 hours for symptomatic cases.
• Prednisolone 20 to 40 mg daily is rapidly effective. Calcitonin 4 units/kg subcutaneously every 12 hours is used for severe cases.
• Bisphosphonates and denosumab are less effective and may cause hypocalcaemia.

Renoprotection. Blood pressure below 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily (monitor calcium and potassium); sodium under 2 g daily; avoid NSAIDs; dapagliflozin 10 mg daily (eGFR at least 25) for proteinuria.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms; transplantation is possible, and granulomas may recur in the allograft.

Monitoring. Creatinine, calcium, urine protein:creatinine ratio and ECG every 2 to 4 weeks during taper, then every 3 months for 2 years; imaging and cardiac assessment yearly; recurrence is common (20 to 30%) when prednisolone falls under 10 mg daily.

Referral and escalation. Nephrology with respiratory and ophthalmology review; cardiology for conduction disease or ventricular arrhythmia; urgent for hypercalcaemic crisis or rapid loss of function.

Special groups

• People of African ancestry: more severe and more chronic disease; higher relapse risk.
• Pregnancy: disease may improve; continue prednisolone and azathioprine; avoid mycophenolate, methotrexate and ACE inhibitors.
• Older adults: lower steroid doses with bone protection; exclude lymphoma.