Kidney and Liver Transplant - Update and Issues
Case 1 -
Acute Tubular Necrosis and Calcineurin Inhibitor Nephrotoxicity
Arthur H. Cohen, Juan Lechago and Cynthia C. Nast
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Acute tubular necrosis usually occurs early in the post-transplant period
as a result of ischemia
. The morphology is similar to that in the native kidney with tubular cells
displaying flattening; however in transplants epithelial cells have been reported to show reduced loss of
proximal cell brush border staining with fewer casts and increased complete cell necrosis . The
epithelial cells slough from the basement membrane into the tubular lumina, and infrequently may leave
denuded areas of basement membrane; in cases of severe tubular injury there is tubular rupture with
extra-tubular Tamm-Horsfall protein in the interstitium. As healing proceeds there is basophilia of the
tubular epithelium and mitotic figures are evident. The interstitium is variably edematous but without
an inflammatory infiltrate. Post-transplant acute tubular necrosis is associated with older donors,
donors and recipients with more severe atheromatous vascular disease, and prolonged cold ischemia time
. This process often is referred to as delayed graft function and is self-limited requiring no
therapy although reduction in cyclosporine levels may speed resolution. When tubular necrosis occurs
after engraftment and lasts for weeks or months it is termed primary prolonged nonfunction, and may
undergo healing by organization with eventual tubulo-interstitial scarring.
Cyclosporine and tacrolimus are calcineurin inhibitors widely used as
anti-rejection agents in renal and hepatic allograft recipients. These agents can induce toxicity in
allograft and native kidneys, with similar mechanisms of action and histologic appearances for the two
. The most common form of acute nephrotoxicity involves the
tubular epithelial cells which display a variant of acute tubular necrosis. Proximal cells are flattened
with loss of brush borders and tubular lumina are relatively dilated. Cells show individual necrosis but
this is not a widespread or pronounced finding. The most diagnostic feature is isometric vacuolization
of proximal tubular epithelium in which the cytoplasm of tubular cells contains small uniform clear
vacuoles. This often affects all cells in a single tubule prolife; however only in a fraction of cases
are the isometric vacuoles found. The interstitium often has mild edema, but no significant lymphocytic
infiltrates are in the interstitium or in the walls of tubules. In patients receiving Neoral and
mycophenolate, prominent perivenous lymphoid aggregates are occasionally identified without tubulitis
. The tubular changes may be accompanied by an arteriolopathy characterized by arteriolar wall
thickening due to muscular hypertrophy. There may be necrosis and drop-out of individual smooth muscle
cells in arteriolar walls; this is followed by the accumulation of insudates (IgM and complement) in a
nodular pattern along the outer aspects of these walls. Juxtaglomerular apparatus are enlarged.
Glomeruli are unremarkable or display ischemic changes with thickening and wrinkling of capillary walls.
Chronic nephrotoxicity extends injury of the tubulo-interstitium to that of
chronic interstitial nephritis. There is a focal "striped" pattern of tubular atrophy with interstitial
fibrosis and a paucity of associated mononuclear inflammatory cells . Tubular inflammation within
atrophic tubules is sparse. Arteriolar changes as described above may be observed, with arteriolar
hyalinization thought to be the most sensitive marker of cyclosporine nephrotoxicity  and further
enlargement of juxtuglomerular apparatus also is seen. Glomerular changes of ischemia are not unusual
and focal and segmental as well as global sclerosis have been described as consequences of cyclosporine
. Abnormalities of arteries are not features of chronic calcineurin inhibitor
toxicity, but it is quite common to have chronic rejection and/or nephrosclerosis occurring in concert
with chronic cyclosporine/tacrolimus nephrotoxicity and it may be difficult to differentiate these
A more infrequent form of nephrotoxicity is hemolytic uremic syndrome which
can be induced by both cyclosporine and tacrolimus, although more commonly by the former
Approximately 15-20% of cases occur in native kidneys of patients receiving calcineurin inhibitors for
reasons other than renal transplantation
. The morphology is identical to other thrombotic
microangiopathies with thromboses in glomerular capillaries, arterioles and less frequently interlobular
arteries. Glomeruli are ischemic to varying degrees, and may have capillary wall double contours,
mesangiolysis, and a lobular appearance. Capillary walls, arterioles and arteries stain for fibrin by
immunofluorescence, and ultrastructurally there are wide subendothelial lucent zones in glomerular
capillary walls with flocculent electron dense and lucent material. Arterioles and small arteries have
muscular hypertrophy, fibrin in the walls and loose mucoid intimal thickening with luminal narrowing. In
severe cases there is focal cortical necrosis.
| || Tubules || Interstitium ||Arterioles|
|Acute Toxicity ||Flattened cells|
| ± edema ||Muscular hypertrophy|
|Chronic Toxicity ||Atrophic ||Striped fibrosis ||Muscular hypertrophy|
|Hemolytic Uremic Syndrome ||Variable ischemic necrosis ||Edema ||Thrombosis|
Fibrin in walls
Loose intimal thickening
The pathogenesis of calcineurin inhibitor nephrotoxicity is likely multifactorial. These agents
cause afferent arteriolar vasoconstriction in a dose dependent manner inducing mild renal ischemia with
subsequent acute tubular injury as a form of ischemic damage and there may be direct tubular toxicity
TGF-beta levels are increased in acute cyclosporine toxicity but not in acute rejection [19 ]
contributing to the acute and chronic tubulo-interstitial damage while the chronic tubulo-interstitial
injury has a vascular etiology. Studies indicate factors released by tubular cells play a role as well 
and there is a shift in expression of collagen types within the interstitium
hemolytic uremic syndrome is more an idiosyncratic abnormality with a multifactorial pathogenesis
encompassing endothelial injury, platelet activation and abnormalities of the clotting and fibrinolytic
systems although the mechanisms are not well understood.
Patients with acute nephrotoxicity present with acute renal failure and usually are biopsied to
exclude transplant rejection. T here may be therapeutic trough levels of drug but nephrotoxicity may
develop due to high peak levels . In some institutions the 2 hour cyclosporine levels are being
measured (C2 levels) to evaluate patients for toxic peak levels ; if these are found treatment consists
of reduction in medication dosage. Infrequently, there may be high peak levels with low trough levels,
and features of acute rejection may coincide with findings of acute calcineuin-inhibitor nephrotoxicity.
The chronic form of nephrotoxicity clinically is associated with a slow deterioration of renal function
over months, and may be more common in patients treated with cyclosporine. Hemolytic uremic syndrome may
occur as the full-blown syndrome with low platelet count, abnormal peripheral smear, hypertension and
renal failure or may be very subtle with few clinical signs. It is crucial to make the diagnosis as
quickly as possible to prevent graft loss secondary to infarction. Therapeutic options include changing
from cyclosporine to tacrolimus , cellcept or sirolimus while reducing or eliminating the offending
agent, and possibly anticoagulation or plasma exchange depending on the severity of the microangiopathic
injury. Patients who have lost a renal allograft to drug-induced hemolytic uremic syndrome have been
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