Table 1.

Histological lesions associated with calcineurin inhibitor (CNI) use, and the differential diagnosis of CNI nephrotoxicity in post-transplantation biopsies

Lesions associated with calcineurin inhibitor useDifferential diagnosis in post-transplantation biopsies
Acute CNI nephrotoxicity
Acute arteriolopathy = renal dysfunction without histological alterationsOther causes of altered renal hemodynamics (e.g. drugs interfering with renal vascular resistance and prerenal azotemia)
Tubular vacuolization (isometric)Osmotic nephrosis due to other agents like mannitol, inulin, glucose, sucrose, dextran, hydroxyethylstarch, urea and radiocontrast agents and also secondary to intravenous immunoglobulins; other causes of tubular ischemia.
Thrombotic microangiopathy (TMA)Recurrent disease (primary HUS/TTP) and other risk factors for TMA like ischemia-reperfusion endothelial injury, renal infections, vascular rejection, anticardiolipin antibodies, malignancies and various other drugs (e.g., mTOR inhibitors, antiviral agents)
Chronic CNI nephrotoxicity
Interstitial fibrosis and tubular atrophy (typically striped)Pre-existing donor injury, aging, ischemia-reperfusion injury, tubulo-interstitial rejection, infection (e.g., UTI, polyomavirus, CMV), chronic ischemia (e.g., renal artery stenosis, size discrepancy in pediatric transplantation), chronic postrenal obstruction, diabetes mellitus
Medial arteriolar hyalinosisPre-existing donor injury, aging, diabetes mellitus, hypertension (in these cases more subendothelial deposition)
Glomerular capsular fibrosisGlomerular ischemia (e.g., renal artery stenosis, chronic arteriolar vasoconstriction, or arteriolar hyalinosis) and other causes of atubular glomeruli (i.e., causes of tubular atrophy)
Global glomerulosclerosisPre-existing donor injury, aging, chronic glomerular ischemia (e.g., renal artery stenosis, arteriolar vasoconstriction, or hyalinosis), recurrent primary disease, de novo glomerular disease, hypertension secondary to tubular atrophy in a late stage
Focal segmental glomerulosclerosis (FSGS)Recurrent primary disease; donor–recipient size discrepancy with hyperfiltration injury; FSGS secondary to other causes of glomerulosclerosis
Juxtaglomerular apparatus hyperplasiaNot well established, but likely other causes of hyperreninemia (e.g., transplant renal artery stenosis)
Tubular microcalcificationsPre-existing donor injury, ischemic tubular injury and acute tubular necrosis, bone and mineral metabolism imbalance, proteinuria
  • HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; TMA, thrombotic microangiopathy; CNI, calcineurin inhibitor; UTI, urinary tract infection; CMV, cytomegalovirus; FSGS, focal segmental glomerulosclerosis.