Calcineurin Inhibitor Nephrotoxicity

Calcineurin inhibitor nephrotoxicity is kidney injury caused by tacrolimus or ciclosporin, used for transplantation, nephrotic syndrome, autoimmune disease and psoriasis. Acute dysfunction affects about 20 to 40% of kidney transplant recipients early, and chronic injury contributes to progressive loss of allograft function in the long term.

It has three forms:

• An acute reversible haemodynamic form (afferent arteriolar vasoconstriction with a dose related fall in glomerular filtration).
• A chronic structural form (arteriolar hyalinosis, striped interstitial fibrosis and glomerulosclerosis).
• An acute thrombotic microangiopathy.

Native kidney injury occurs in about 10 to 30% of patients treated for more than 2 years with ciclosporin (risk rises with ciclosporin above 5 mg/kg daily). Other effects are hyperkalaemia, hypomagnesaemia, distal renal tubular acidosis, hypertension, hyperuricaemia and diabetes.

Pathophysiology. Calcineurin inhibition raises endothelin and thromboxane and lowers prostacyclin and nitric oxide production, causing afferent vasoconstriction. Sustained exposure leads to arteriolar hyalinosis, ischaemic glomerulosclerosis, tubular injury and fibrosis, with transforming growth factor beta driving interstitial fibrosis. Thrombotic microangiopathy follows endothelial injury.

• Rise in creatinine of 20 to 30% or more within days to weeks of starting, increasing the dose, or adding an interacting drug (azoles, macrolides, diltiazem, verapamil, grapefruit); falls within days of dose reduction.
• Hypertension, hyperkalaemia, hypomagnesaemia, metabolic acidosis, hyperuricaemia, hyperglycaemia, tremor, headache, hirsutism and gingival hyperplasia (ciclosporin).
• Chronic injury: slowly rising creatinine, mild proteinuria, worsening hypertension.
• Thrombotic microangiopathy: rising creatinine with haemolysis, falling platelets and hypertension.
• Extrarenal toxicity: neurotoxicity (posterior reversible leukoencephalopathy syndrome), diabetes (tacrolimus), dyslipidaemia (ciclosporin).

Red flags

• Creatinine above 30% over baseline.
• Trough level over the target range, or a recent interacting drug.
• Haemolysis, thrombocytopenia and rising creatinine (thrombotic microangiopathy).
• Severe headache, visual disturbance, seizures.
• Potassium above 6.0 mmol/L.

• Trough (12 hour) blood level of tacrolimus or ciclosporin, creatinine, eGFR, potassium, magnesium, bicarbonate, glucose, uric acid, full blood count, lactate dehydrogenase, haptoglobin, blood film.
• Review drugs and food that alter levels: inhibitors (diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, voriconazole, ritonavir, grapefruit) and inducers (rifampicin, phenytoin, carbamazepine, St John's wort), diarrhoea (raises tacrolimus levels), and missed or altered doses.
• Kidney ultrasound and Doppler to exclude obstruction and vascular causes; urine protein:creatinine ratio.
• Kidney biopsy for unexplained decline or when rejection is possible: acute toxicity shows isometric tubular vacuolisation; chronic toxicity shows nodular arteriolar hyalinosis, striped fibrosis and global glomerulosclerosis; thrombotic microangiopathy shows thrombi and endothelial swelling; compare with rejection (tubulitis, endarteritis, C4d staining) and BK virus (inclusions, SV40 staining).

Differential diagnosis

• Acute rejection, BK virus nephropathy, recurrent glomerular disease, renal artery stenosis, obstruction, volume depletion, drug interactions with other nephrotoxins, thrombotic microangiopathy from other causes.

First line: confirm toxicity and reduce exposure

• Check the trough level and interacting drugs first. When the level is over the target, reduce the dose by 25 to 50% and recheck the level in 3 to 5 days, then weekly until stable.
• Reasonable trough targets: tacrolimus 5 to 8 ng/mL in stable transplant recipients (8 to 12 ng/mL in the first 3 months, 4 to 6 ng/mL with low dose regimens plus everolimus); ciclosporin 100 to 200 ng/mL; in native kidney disease, tacrolimus 5 to 8 ng/mL and ciclosporin 80 to 120 ng/mL (3 to 5 mg/kg daily as the usual ceiling).
• Correct volume depletion; stop other nephrotoxins (NSAIDs, aminoglycosides, contrast); stop or avoid interacting drugs.
• If creatinine remains above 30% over baseline after dose reduction for 1 to 2 weeks, repeat the biopsy to define the cause.

Minimisation and conversion (transplant recipients, with the transplant team)

• Add everolimus 0.75 to 1.5 mg twice daily (trough 3 to 8 ng/mL) with a 50 to 75% reduction in tacrolimus.
• Switch to belatacept 5 mg/kg intravenously every 4 weeks after an initial loading schedule, in selected patients with stable function and low immune risk.
• Mycophenolate mofetil 1 g twice daily may allow calcineurin inhibitor reduction.
• Switch ciclosporin to tacrolimus when hirsutism, gingival hyperplasia or dyslipidaemia is a problem, and tacrolimus to ciclosporin when diabetes or tremor is severe.
• Avoid withdrawal in patients with high rejection risk.

Thrombotic microangiopathy

• Reduce or stop the calcineurin inhibitor and substitute an alternative (everolimus or belatacept).
• In severe cases give plasma exchange (1 plasma volume daily with fresh frozen plasma for 5 to 7 days).
• For refractory complement mediated disease give eculizumab 900 mg weekly for 4 doses, 1200 mg at week 5, then every 2 weeks.
• Control blood pressure and treat the underlying contributors.

Associated metabolic effects

• Hyperkalaemia: restrict potassium and stop other potassium raising drugs.
• Use sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily (maximum 15 g).
• Fludrocortisone 0.1 mg daily where acidosis and hyporeninaemic hypoaldosteronism coexist.
• In emergencies: calcium gluconate 10% 10 mL intravenously over 10 minutes, insulin 10 units with glucose 25 g, and salbutamol 10 to 20 mg nebulised.
• Hypomagnesaemia: magnesium glycerophosphate 4 mmol (about 97 mg elemental magnesium) one to three times daily, or magnesium oxide 400 to 800 mg daily; avoid in kidney failure; recheck in 1 week.
• Metabolic acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Hypertension: amlodipine 5 to 10 mg daily (preferred; does not raise levels), ramipril 2.5 to 10 mg daily with potassium checks; avoid diltiazem and verapamil (raise levels), blood pressure below 130/80 mmHg.
• Hyperuricaemia: allopurinol 100 mg daily (avoid with azathioprine).
• Post-transplant diabetes: monitor glucose; consider conversion from tacrolimus.
• Dyslipidaemia: atorvastatin 10 mg maximum (with ciclosporin) or fluvastatin or pravastatin, as ciclosporin raises statin levels.

Neurotoxicity. Reduce or stop the calcineurin inhibitor; control blood pressure; treat seizures with levetiracetam 500 mg twice daily (adjusted for eGFR).

Monitoring. Trough levels at each dose change and 5 to 7 days after any interacting drug starts or stops; creatinine and potassium weekly for the first 4 weeks after a change, then at each visit (every 4 to 8 weeks); magnesium monthly; blood pressure, glucose and lipids every 3 months; surveillance biopsies at transplant centres.

Referral and escalation. Transplant nephrologist for any creatinine rise above 25% in a recipient; urgent for thrombotic microangiopathy, neurotoxicity or hyperkalaemia above 6.5 mmol/L.

Special groups

• Children: calcineurin inhibitors in nephrotic syndrome for periods under 2 years with biopsy review when used longer.
• Pregnancy: tacrolimus and ciclosporin are acceptable; levels fall in the third trimester (check every 2 to 4 weeks).
• Older adults: lower target levels and stricter blood pressure control.
• Autoimmune disease (lupus, nephrotic syndrome, vasculitis): keep trough levels at the low end of the range; repeat biopsy after 2 years of treatment or if eGFR falls by more than 25%.