4. You were asked to review a 35-year-old man who received a kidney transplant 3 years ago. His baseline s Cr is 170 µmol/L on triple immunosuppression (cyclosporine based). He has seen the GP for possible chest infection. He was treated with erythromycin TDS for 7 days, with improvement of the chest symptoms, but he noticed reduction of the urine output. His repeat s Cr was 530 µmol/L. Biopsy showed:
- Would you manage this case differently?
- Describe the histology?
- What is the likely diagnosis?
- Describe the mechanism of injury?
Dear All
Still, no one answered how vacuolation in acute CNI toxicity happened.
the mechanism of injury is due to dilatation of endoplasmic reticulum
Isometric tubular vacuolization could be the consequence of relative ischemia caused by afferent arteriolar vasoconstriction, but the possibility that direct effects of calcineurin inhibition in tubular epithelial cells cause alterations in endoplasmic reticulum structure and function .
Acute CNIs nephrotoxicity maybe sometimes by caused acute arteriolar toxicity which non specifically may manifest as arteriolar wall vacuolization, which is a morphologic expression of arteriolar vasospasm.
https://reader.elsevier.com/reader/sd/pii/S246802491730428X?token=5EFF31D8AA210AE03D64BA1579944B6E341F012DAA48013A335AE1A343B637144F0D14FA559B9211BD9FCC8BA8178156&originRegion=eu-west-1&originCreation=20211203185729
These vacuoles are composed of enlarged endoplasmic reticulum. As the name isometric implies, the vacuoles are small and evenly distributed within the cytoplasm.
In addition to the enlarged endoplasmic reticulum, the affected tubules can sometimes show
giant mitochondria.
Tubular vacuolization is not highly specific for acute CNI toxicity and has been documented
in allograft biopsies of patients with CNI-free regimens, renal ischemia, or even in association
with rejection. Isometric vacuolization with more pronounced swelling of the tubular cytoplasm can be seen in “osmotic nephrosis,” which can occur following treatment with i.v. Ig, radiocontrast, or
dextran. In contrast to isometric vacuolization attributed to CNI, the vacuoles in osmotic nephrosis are usually composed of lysosomes, which contain the culprit agent that enters the cytoplasm via pinocytosi
The processes by which CNIs lead to isometric tubular vacuolization are currently not known. Isometric tubular vacuolization could be the consequence of relative ischemia caused by afferent arteriolar vasoconstriction, but the possibility that direct effects of calcineurin inhibition in tubular epithelial cells cause alterations in endoplasmic reticulum structure and functioning cannot be excluded
Cyclosporine characteristic tubular vacuolization (TV) is an endoplasmic reticulum (ER) in origin. However, the cellular events of CsA-induced TV and CsA-induced ER remained unclear. Cheng CH et al had shown that vacuolization occurred through CsA-induced ER stress and involved ER integrated stress response-related proteins (Bip/Grp78, ATF6, IRE1 and CHOP), in which Bip/Grp78 overexpressed on the membrane of TV and was essential for TV formation. Suppression of Bip/Grp78-enhanced CsA-induced cell death and CsA-induced TV formation and Bip/Grp78 overexpression had a characteristic striped pattern in the tubulointerstitium.
Reference
Cheng CH, Shu KH, Chang HR, Chou MC. Cyclosporine-induced tubular vacuolization: the role of Bip/Grp78. Nephron Exp Nephrol. 2012;122(1-2):1-12. doi: 10.1159/000346956. Epub 2013 Feb 15. PMID: 23428559.
The small, uniformly sized tubular epithelial cell cytoplasmic vacuoles are caused by toxic levels of the calcineurin inhibitors cyclosporine and tacrolimus and are due to dilatations of smooth endoplasmic reticulum by aqueous fluid
Reference
Douglas A. Charney, Madhu Bhaskaran, and Ernesto Molmenti.
Calcineurin inhibitor toxicity in a renal transplant recipient
NDT Plus. 2009 Apr; 2(2): 175–176.
Oxford University Press
Ballooning of the cytoplasm as a results of the toxic injury to the tubular epithelium.
●●How vacuolation happens?
Microscopic changes in the renal biopsy in acute CNI toxicity include isometric tubular vacuoles in proximal tubules (due to dilated endoplasmic reticulum with giant mitochondria, large lysosomes) and microcalcifications. These could be due to afferent arteriole vasoconstriction or even due to direct effect of cni on the tubules. The exact cause could not be established yet.
●The arteriolar hyalinosis is the most reliable diagnostic marker of CNI toxicity.
This is due to
arteriolar smooth muscle cell degeneration, endothelial cell swelling, intimal thickening, variable hyaline or mucoid deposits which narrow lumen
●Both findings are
Dose dependent and reversible
☆☆References:
https://www.ncbi.nlm.nih.gov/pubmed/?term=Cyclosporin+A+toxicity+%5Btitle%5D
The mechanism of vacuolation in acute CNI toxicity is due to relative ischemia caused by afferent arteriolar vasoconstriction. It is also thought to be due to direct effect of CNI on the structure and function of endoplasmic reticulum in tubular epithelial cells. There is enlarment of endoplasmic reticulum with increased lysosomes.
Reference:
Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508.
Dear All
The main differential diagnosis of acute CNI toxicity causing acute allograft injury is acute rejection either cell mediated or antibody mediated rejection.
One of the mechanisms of acute CNI toxicity is vascular toxicity in two ways acute arteriolopathy and thrombotic microangiopathy.
Acute Arteriolopathy are lesions confined to afferent arterioles and There is swelling and vacuolation of endothelial cells. In cell mediated vascular rejection Type IIA,IIB and type III according to Banff classification with mild, moderate and severe intimal arteritis.
Thanks, Mohamed
But this is not what I asked for
Tubular vacuolation can occur as a result of osmotic injury caused by IVIG , manitol, IV contrast.
Acute CNI toxicity: acute arteriolopathy, tubular vacuolization, TMI
Chronic CNI toxicity: IFTA( striped), medial arteriolar hylinosis, glomerular capsular fibrosis, global sclerosis, FSGS, juxtaglomerular apparatus hyperplasia, & tubular micro calcification
acute CNI toxicity can cause TMA
yes it can happen , when the patient has high trough or C2 , with slight increase in serum creatinine, then i decrease dose of cyclosporin , this may induce acute cellular rejection , biopsy can be mixed of both
causes of vacuolation: drug induced or exposure to pathogen viral or bacterial, or may happen spontaneously without any change in the surrounding environment and neighboring cell is not affected, may be as a part of programmed cell death.
acute toxicity:
enlarged ER with defect in protein synthesis, vacuolation of the cells , increase in vasoconstrictors like RAS, thromboxan A2, endothelin, and decrease in vasodilators like PGE2, NO…also there is a direct toxicity of tubular epithelium, and also cyclosporin block mitochondrial permeability pores leads to giant mitochondria and vacuolation of cells.
chronic toxicity :
stripped interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis, may be tubular micro-calcification, glomerular sclerosis. this picture is not specific to CVI toxicity , but related to chronicity, CNI one of the causes.
J. R. Chapman. Chronic Calcineurin Inhibitor Nephrotoxicity—Lest We Forget. 29 March 2011.
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Yes differ in the following :
1- Acute CNI toxicity is dose related occur with higher level of CNI, while chronic CNI toxicity is duration related to chronic use of CNI low or high dose , although chronic CNI toxicity tend to occur earlier in patients taking higher doses
2- Acute CNI toxicity is reversible once the dose is reduced while chronic CNI toxicity is largely irreversible.
3- Pathogenesis
⦁ It is suggested that the primary event responsible for acute or chronic damage related to CNI is vascular lesions, CNI produce endothelial dysfunction that cause decreased production of vasodilators (prostaglandins and nitric oxide) and increased production of vasoconstrictors (endothelin and thromboxane) leading to afferent and efferent arteriolar vasoconstriction and subsequent tubular ischemia, injury, atrophy and interstitial fibrosis
⦁ CNI increase oxidative stress with production of ROS thus adding to injury.
⦁ In chronic CNI toxicity there is increased expression of osteopontin which is secreted from tubular epithelium and cause chemotaxis of macrophages and TGF-beta which is secreted due to decreased NO secretion and local increase in angiotensin II, TGF- beta stimulates extracellular matrix production leading to chronic damage, CNI increase apoptosis leading to chronic damage
⦁ SO… CCB may be preferred for treatment of HTN associated with acute CNI toxicity (promote arteriolar vasodilatation) while ACE inhibitors and ARBS are preferred for treatment of HTN associated with chronic CNI toxicity (targeting angiotensin II)
4- Pathology
⦁ In acute CNI toxicity renal biopsy usually shows tubular vacuolization, acute arteriolopathy and vascular lesions resembling TMA
⦁ In chronic CNI toxicity renal biopsy shows tubular vacuolation, tubular atrophy, obliterative arteriolopathy (due to endothelial damage), glomerular collapse, global and focal FSGS, striped fibrosis (focal areas of interstitial fibrosis)
Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
CNI toxicity can happen with histological evidence of cell-mediated rejection in the following conditions :
1. Chronic CNI toxicity can occur with small dose of CNI that produce rejection so biopsy may demonstrate CMR in association with chronic lesions related to CNI toxicity which can be interpreted in the context of rejection
2. Acute CNI toxicity can occur due to non compliance in other immunosuppressive regimens such as MMF, corticosteroids.
What are the other causes of vaculation?
tubular vacuolation usually interpreted as a drug side effect
1. Osmotic nephrosis related to iv mannitol, iv dextran, IVIG, and some case reports incriminating SGLT2.
2. Post iv contrast especially ionic dye
3. Phospholipidosis (PLD) which is reversible accumulation of phospholipids due to certain drugs such as aminoglycosides or tricyclic antidepressants.
4. May be a physiological finding or artifact due to autolysis or poor fixation .
Well done Sherif very good grasp of the subject specially high lighting the diff. between dose and duration.
please xplain how as you stated ( acute CNI toxicity can occur due to non complience with steroids and MMF?)
Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
What are the other causes of vacuolation?
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
CNIs have a narrow therapeutic window, with low levels increasing the risk of acute allograft rejection while high levels increase the risk of nephrotoxicity that may lead to acute or chronic kidney allograft injury.
CNI toxicity can co-exist with acute cellular rejection its due to immune mediated tubular injury with ischemic vascular endothelial injury and thrombotic microangiopathic injury .
Acute CNI -Nephrotoxicity:
Its reversible, dose dependent lead to direct tubular injury due to acute hemodynamic effect, CNI-induced vascular endothelial injury and Arteriolar vasoconstriction lead to endothelial vascular ischemia with lysosomal swelling or mitochondrial swelling(seen by electron microscopy) with the isometric tubular epithelial cells vacuolation with focal or diffuse bubbly appearing tubules this is not pathognomonic for CNI injury as it can occur with other osmotic agents like contrast media , IVIG infusion , mannitol , Dextran, recent repoets of osmotic nephrosis with acute tubular injury with the use of SGLT2 inhibitors, some antiviral like tenovifor.
CNI – induced thrombotic mircoangiopathy( TMA ).
New urinary and blood biomarkers are of clinical interest like ICAM 1, fascin-1 levels from kidney-transplanted patients under CNIs treatment and show promise in detecting CNI-induced nephrotoxicity.still in pre-clinical phasetrails.
Chronic CNI toxicity:
progressive irreversible, usually dose and duration dependent lead to Chronic allograft dysfunction and ESKD
combination of chronic hemodynamic effects and direct tubular effects. CNI-induced vascular endothelial injury and Arteriolar vasoconstriction leads to repeated episodes of allograft ischemia and chronic kidney hypoperfusion, which can further worsen in the Prescence of chronic salt wasting tubulopathy with chronic hypomegesemia,CYP3A5*1 polymorphism (expressors of CYP3A5; 236) had a higher risk of developing chronic CNI nephrotoxicity compared with non expressors (CYP3A5*3/*3) nephrotoxicity due to higher peak drug exposures and increased circulating CNI metabolites.
Who to differentiate between CNI-induced nephrotoxicity and chronic allograft nephropathy?
Key kidney biopsy findings include obliterative arteriolopathy/hyalinization of the afferent arteriole, ischemic collapse or glomerular scarring, tubule vacuolization, focal and global segmental glomerulosclerosis, focal interstitial fibrosis associated with macrophage influx, and tubular (striped fibrosis).
The severity of biopsy findings correlates with dose and duration of CNI use.
Interventions can lower Chronic CNI toxicity:
1-The non- Dihydropyridines CCBs, diltiazem and verapamil, can be used as CNI sparing agents to lower the total CNI dose with lower cost.diltiazem also lower the CNI induced vasoconstriction yet thereis definitive evidence that diltiazem prevents chronic CNI nephrotoxicity.
2-RAAS blockade attenuates CSA induced interstitial fibrosis and arteriolopathy in rats. (3) ARBs decrease expression of TGFβ, a cytokine which plays a central role in causing CNI-induced interstitial fibrosis. (4) However, a recent meta-analysis did shows inadequate evidence to determine if RAAS blockade effective in Chronic CNI toxicity.
3-CNI -Free , CNI minimizing IS protocol by using belatacept has been shown to stabilize eGFR in patients with chronic CNI nephrotoxicity with increasing acute rejection .
4- statin use ,magnesiums supplementation.
References:
1-The Many Faces of Calcineurin Inhibitor Toxicity – What the FK?
Samira Farouk, MD, MS1,2, Joshua L. Rein, DO1
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New
York, NY, Recanati-Miller Transplant Institute, Mount Sinai Hospital, New York, NY
2-Fascin-1 is released from proximal tubular cells in response to calcineurin inhibitors (CNIs) and correlates with isometric vacuolization in kidney transplanted patients.
Conxita Jacobs-Cachá,1 Irina B Torres,2 Joan López-Hellín,1 Carme Cantarell,2 María A Azancot,2 Antonio Román,3 Francesc Moreso,2 Daniel Serón,2 Anna Meseguer,1,4,* and Eduard Sarró1,
3-Acute kidney injury pathology and pathophysiology:
a retrospective review Joseph P. Gaut and Helen Liapis.CKJ,
4-Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling
Raquel Rodrigues-Diez,1 Cristian González-Guerrero,1,* Carlos Ocaña-Salceda,1,* Raúl R. Rodrigues-Diez,1 Jesús Egido,1,3 Alberto Ortiz,1,3 Marta Ruiz-Ortega,2 and Adrián M. Ramosa,1Department of Pathology and Immunology and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
5-Calcineurin Inhibitor Nephrotoxicity
Maarten Naesens,*† Dirk R. J. Kuypers,* and Minnie Sarwal†*Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; †Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
Well done Saja an issue here concerning some drugs:
would you consider the over routine prescription ofPPI proton pump inhibitors for PKT patients a very safe events as to:
effect on prox. tubular secretion of creatinine
when combined with other drugs as fluconazole
effect of liver affection when combined with cyclosporine
just keep those in mind when following daily chemistry
proton pump inhibitor shold not consider safe drug and not consider for over routine prescrpition , so many side effects in relation to chronic use of PPI in general it can cause acute interstitial nephrtitis and slient cause of CKD, in kidney transplantion can worsning salt wasting nephropathy in combination with CNI in particular hypomeganesemia as its known common side effect of PPI use.
also pantprazole can augmnet the cyclsoprine C0 level as compared to esomprazole and shoud consider dose adjustment as safety precuation
references :Esomeprazole vs pantoprazole effects on cyclosporine levels in kidney transplantation: A randomized clinical trial
Doaa El-Bohy 1, Magdy El Sharkawy 2, Soheir Abo-Elazm 3, Sara Shahin 4, Waleed Bchari 2, Azza Mancy 5, Manal El Hamamsy 4
vacuolization is due to dilatations of smooth endoplasmic reticulum by aqueous fluid (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421359/)
the pattern of acute is different from chronic in that:
”’Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy. ”‘ copied from: Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts DOI: 10.1038/ncpneph0225
chronic CNI toxicity features in tissue biopsy are nonspecific and non-pathognomonic like arteriolar hyalinosis and IFTA as it can happen in other conditions like, old donor graft with arteriolar hyalinosis, DM, Chronic allograft nephropathy and most of the cases with chronic T cell mediated rejection with IFTA often diagnosed as chronic allograft nephropathy (CAN)and assumed to be caused by CNI toxicity.
in one study(2) found the association of the arteriolar hyalinosis (ah)score with chronic glomerular diseases in late biopsies has been underestimated previously because of two errors,the assumption that ah lesions always reflect CNI drug toxicity and the failure to recognize C4dnegative ABMR (1) resulting in the interpretation of ah3 lesions in deteriorating late kidney transplants as CNI drug toxicity. When most ABMR could not be recognized because the histology consensus insisted that C4d was required for the diagnosis of ABMR. but recently the C4D negative ABMR more appreciated .
Misinterpretation of ah lesions has serious effect on patient management as CNI minimization protocol may negatively impact the graft survival.
one of the unmet goals in CNI-free regimen by using belatocept is the increased rate of acute rejection (3).
REFERNCES:
1-Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326–2333
2-Hyalinosis Lesions in Renal Transplant Biopsies:
Time-Dependent Complexity of Interpretation
G. Einecke1, J. Reeve2,3 andP. F. Halloran2,3,4,*
American Journal of Transplantation 2017; 17: 1346–1357
3-An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed.
Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
CNI has a narrow therapeutic index so in low levels it will cause rejection and the higher levels leads to toxicity
What are the other causes of vaculation?
IVIG, Dextran, Osmotically active substances
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Acute CNI lead to acute kidney injury resulting from acute vasoconstriction and reduction in renal blood flow which is usually reversible after reduction of the CNI dose. Histologically it can be seen as tubular injury and vaculation, also TMA can be caused by acute CNI toxicity.
Chronic CNI toxicity leads to irreversible damage seen as IFTA ( striped fibrosis) , glomerulosclerosis and arterial hyalinosis
Acute CNI toxicity characterized by early necrosis and hyalinosis in smooth muscle cells of afferent arterioles and /or isometric vaculation of the proximal straight tubules but TMA is a rare manifestation.
Chronic toxicity the damaged smooth muscle cells of the afferent arterioles will changed to beaded hyalin deposits causing it’s bulging into the adventitia, striped fibrosis in the interstitium and tubular atrophy.
Chronic CNI toxicity leads to chronic allograft nephropathy.
Vaculation can occur in CNI toxicity and ischemic tubular injury.
-CNI related nephrotoxicity is due to acute arteriolopathy which is related to acute arteriole vasoconstriction, mainly the afferent arterioles.
In general CNI related renal toxicity is thought to be induced by several factors, resulting from a combination of an increase in vasoconstrictive factors (endothelin and thromboxane), activation RAAS, decrease in vasodilator factors (nitric oxide (NO) and prostacycline), and formation of free radicals.
-Vacuolization of proximal tubular epithelial cells can be induced by various kinds of mechanisms such as ischemia, hypokalemia, hyperosmolarity and lipid accumulation.
Recently an article has been published on SGLT2-induced proximal tubular vaculization in 3 obese patients.
references:
Zhou C, Yool AJ, Nolan J, Byard RW. Armanni-Ebstein lesions: a need for clarification. J Forensic Sci. 2013;58, S948. https://doi.org/10.1111/j.1556-4029.2012.02274.
Zhou C, Vink R, Byard RW. Hyperosmolarity induces Armanni-Ebstein-like renal tubular epithelial swelling and cytoplasmic vacuolization. J Forensic Sci. 2017;62(1):229–32.
Parai JL, Kodikara S, Milroy CM, Pollanen MS. Alcoholism and the Armanni-Ebstein lesion. Forensic Sci Med Pathol. 2012;8(1):19–22.
10.1007/s13730-021-00609-7
■Question 1
Although the typical vascular lesion of AMR is fibrinoid necrosis or transmural endarteritis [7], TMA is also occasionally seen in severe Acute Mediated Rejection ((AMR)).
The prevalence of TMA in kidney allografts was reported to be 4–46% of AMR cases.
CNI AS WELL CAUSE
TRANPLANT ARTERIOPATHY AND TMA.
References :
Lobo PI, Spencer CE, Stevenson WC. Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin. Transplantation. 1995; 59(3): 357–60. 8 Lefaucheur C, Nochy D, Hill GS, SuberbielleBoissel C, Antoine C, Charron D, et al. Determinants of poor graft outcome in patients with antibody-mediated acute rejection. Am J Transplant. 2007; 7(4): 832–41.
N.B.
●It should be noted that not only rejection but also additional histopathological findings, such as CNI toxicity and polyomavirus nephropathy may overlap.
●High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes.
■Question 2 :
OTHER CAUSES OF TUBULE VACUOLIZATION :
• Nephrotoxicity Secondary
to CNI & IVIG
• Rejection : TCMR while the ABMR is mimicking CNI toxicity in that both can make TMA and GBM DUBLICATION.
• Mannitol
• Injection of radiographic contrast media.
■Question 3
●ACUTE CNI pathological pattern :
•Acute arteopathy.
•Tubular vacuolization.
● CHRINIC CNI :
•Obliterative arteriopathy
•Ischemic collapse
• Scarring of glomeruli
•Tubular vacuolization
• Focal segmental or global glomerulosclerosis
• Focal areas of tubular atrophy and interstitial fibrosis producing picture of stripped fibrosis.
• Arteriolar hyalinosis that can be reversible if occured within the 1st 6 months.
Or irreversible if occured within 3 years.
(NB THE CHRONIC CNI TOXICITY CAN BE MINIMIZED BY USING —> ANTI _ TGF beta therapy.
Interestingly
Losartan as well as AcEi and ArBs may protect against arteriopathy
While
Losartan , hydralazine and furosemide may reduce interstitial fibrosis of cni toxicity
1. Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
Yes, CNI has narrow therapeutic levels which may lead to CNI toxicity. Subclinical rejection usually involved cellular rejection which may seen together with CNI toxicity.
2. What are the other causes of vaculation?
Osmotic nephrosis agents like mannitol, inulin, glucose, sucrose, dextran,hydroxyrethylstarch, urea radiocontrast agents, tubular ishaemia due to other causes and secondary to immunoglobulins
These vacuolization can be differentiate by varying sizes of vacuoles compared to isometric vacuolization in CNI toxicity.
3. Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Yes,
Acute CNI nephrotoxity
• Acute afferent arteriolapathy: endothelial swelling/vacuolation: necrosis and early stage hyaline replacement of individual myocytes
• Tubulopathy: small, evenly distributed vacuoles mainly in the proximal straight tubules
• Thrombotic microangiopathy
Chronic CNI nephrotoxicity
• Hyaline arteriopathy: myocytes are replaced by beaded hyaline deposits that bulge into the adventitia
• Non-specific segmental or global glomerular sclerosis
• Striped interstitial fibrosis and tubular atrophy
4. Why do we have these vaculations in CNI toxicity? what is the mechanism of the vaculation?
Isometric vacuolization of the tubular cytoplasm happens due enlargement of the endoplasmic reticulum and increased lysosomes. The exact process which lead to vacuolization are not known. It could be the consequences of relative iscahemia caused by afferent arteriolar vasoconstriction. It could be also due to direct effect of CNI in tubular epithelial cells that results in change in endoplasmic reticulum structure and functioning.
1. Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
Yes. It can happen in a setting with chronic CNI toxicity (which depends on duration of CNI intake) and patient developing acute cellular rejection due to sub-optimal levels of CNI.
2. What are the other causes of vacuolation?
The other causes of vacuolation include tubular ischemia, drugs like radiocontrast, IVIG, dextran, mannitol, glucose, sucrose, inulin, urea and hydroxyethylstarch causing osmotic nephrosis.
3. Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Yes:
Patterns of acute CNI toxicity: Acute arteriolopathy, tubular vacuolation and thrombotic microangiopathy.
Patterns of chronic CNI toxicity: Striped interstitial fibrosis and tubular atrophy, medial arteriolar hyalinosis, glomerular capsular fibrosis, global glomerulosclerosis, FSGS, juxtaglomerular apparatus hyperplasia and tubular microcalcifications.
Reference:
Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508.
Mechanism of isometric cytoplasmic vacuolization:
isometric cytoplasmic vacuolization of the proximal tubules, which is usually focal in nature. These vacuoles are composed of enlarged endoplasmic reticulum. As the name isometric implies, the vacuoles are small and evenly distributed within the cytoplasm .In addition to the enlarged endoplasmic reticulum, the affected tubules can sometimes show giant mitochondria.Contrary to acute arteriolopathy, morphologic manifestations of CNI-induced acute tubular toxicity may be seen in protocol biopsies obtained from transplant patients without overt allograft dysfunction.Therefore, some investigators do not consider them as critical precursors for chronic allograft damage.Tubular vacuolization is not highly specific for acute CNI toxicity and has been documented in allograft biopsies of patients with CNI-free regimens, renal ischemia, or even in association with rejection.Isometric vacuolization with more pronounced swelling of the tubular cytoplasm can be seen in “osmotic nephrosis,” which can occur following treatment with i.v. Ig, radiocontrast, or dextran.In contrast to isometric vacuolization attributed to CNI, the vacuoles in osmotic nephrosis are usually composed of lysosomes, which contain the culprit agent that enters the cytoplasm via pinocytosis.
1-CNI toxicity ,follow cyclosporine level during erythromycin course ,and modify the dose accordingly
2-vacuolation of renal tubules
3-CNI toxicity
4- Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy.
Studies have shown that due to reduced diameter of the small vasculature, the renal parenchyma undergoes degenerative changes .Furthermore, these regions of the kidneys are more susceptible to injury due to their limited oxygen availability . Reduced oxygen in the renal tissue promotes the development of chronic kidney disease additionally to the nephrotoxicity induced by CNI treatment. Low oxygen leads to renal hypoxia and therefore also to ATP starvation. These will then activate fibrosis pathways. Interstitial fibrosis around the tubules in the kidney augments the diffusion distance between blood and tissue. Cippa showed that also patients with high domicile altitude show more progressive ah lesions than patients with lower residential altitude .
Yes , this case most probably has CNI induced nephrotoxicity diagnosed by acute elevation in serum creatinine level.this CNI toxicity is induced by the use of erythromycin drug which is a potent hepatic enzyme inhibitor ,its use expose patient to high CsA drug level and toxicity .
This patient treated by
Stop erythromycin if antibiotic is needed , we has to use drug with no interaction with CsA.
Reduce the dose of CsA .
CsA drug level renal function test monitoring .
CsA nephrotoxicity is usually reversible .
Some report suggest use of hepatic enzyme inducer ( phenytoin,phenobarbital) in sever toxicity .
Extracorporeal modalities are not effective because CsA protein bound .
This is renal biopsy ,showing renal tubules , the tubules shows diffuse epithelial isometric vacuolization.
CNI toxicity ,
The macromolecules enter the proximal tubules across the luminal surface, and cause tubular cell swelling before accumulating in lysosomes, visualized as vacuoles by light microscopy. Tubular epithelial cell swelling may contribute to obstruction of the tubular lumen, with decreased urine flow resulting in AKI.
Causes
1- Calcineurin inhibitor nephrotoxicity
2- Osmotic tubular injury is due to exposure to hyperosmolar agents that are intravenously infused. Hyperosmolar radiocontrast agents, hydroxyethyl starch, mannitol, and IVIG are common causes of this injury.
Acute rejection is the major obstacle for allograft survival in nonimmunosuppressed animals. T-cell activation, which is the main step in initiating rejection following solid organ transplantation, needs 3 sequential signals.1 Signal 1 requires interaction of a major histocompatibility complex molecule that carries an allopeptide on an antigen-presenting cell with a T-cell receptor on the recipient T cell. Signal 2 is provided by the binding of costimulatory molecules on an antigen-presenting cell (e.g., CD80/CD86) with their T-cell counterparts (e.g., CD28). Signals 1 and 2 activate the downstream pathways of calcium-calcineurin, RAS-mitogen-activated protein kinase, and nuclear factor-kappa B pathways, which trigger the expression of several cytokines, including interleukin (IL)-2. Signal 3 follows IL-2/IL-2 receptor binding, which activates mammalian target of rapamycin (mTOR) that leads to T-cell proliferation and clonal expansion. Fully activated T cells can then initiate T-cell–mediated rejection and/or activate B cells to trigger antibody-mediated rejection.1, 2 Disrupting T-cell activation has been the target for immunosuppressive medications in solid organ transplantation. The development of potent immunosuppressive medications has dramatically decreased the incidence of early acute rejection and improved short-term allograft survival.3 Despite this significant improvement, long-term allograft survival remains suboptimal. This may be largely attributed to the limitations of the current immunosuppressive agents related to their toxic side effects and inability to control late smoldering rejection.4
This is a CNI toxicity
1- AKI following administration of erythromycin which increase cyclosporine level by inhibiting cytochrome P450.
2- Renal biopsy shows tubular vacuolization ( typical for CNI toxicity)
Mechanism of injury
CNI produce afferent and efferent arteriolar vasoconstriction with decreased production of vasodilators (prostaglandins and nitric oxide) and increased production of vasoconstrictors (endothelin and thromboxane) leading to tubular ischemia and tubular injury, more over CNI increase oxidative stress with production of ROS thus adding to injury.
Management
1. check cyclosporine level
2. Stop erythromycin and decrease the dose of cyclosporine keeping the level between 50-150 and follow up creatinine level. AKI in cyclosporine toxicity is usually reversible once the drug dose is reduced since this effect is dose related
3. Adequate hydration
4. Hold ARBS temporary if used, consider switch to amlodipine if no significant proteinuria as CCB was found to decrease the nephrotoxic effect of CNI
5. Monitoring of electrolytes and blood gas is recommended since there is increased incidence of hyperkalemia and RTA -4
This case of drug interactions due use of erythromycin enzyme inhibition causing high
Csa level,
Would stop erythromycin. change less toxic drugs for chest infection.
Acute arteriolopathy due arteriole vasoconstriction.
A case of cyclosporine toxicity based on :
-Acute deterioration of kidney function following use of erythromycin through raising cyclosporine level by inhibiting cytochrome P450.
-Histopathology picture of CNI toxicity ;tubular vacuolation without clue of TCMR or ABMR.
Management
Cyclosporine level determination, discontinuation of erythromycin with cyclosporine doe reduction to 50-150with monitoring effect on serum creatinine. AKI expected to resolve .In addition, well hydration ,avoidance of any nephrotoxic agent, and replacing ARBS with CCB .Acid base and electrolyte monitoring especially for expected hyperkalemia and renal tubular acidosis.
Mechanism of injury
-CNI cause endothelial cell dysfunction ,leading to decreased VD (PGE&NO)and increased VC (endothelin& thromboxane),leading to tubular ischemia and injury.
-CNI increase oxidative stress and ROS
Would you manage this case differently?
Patient on CNI (cyclosporine) w is metabolized by cytochrome p450 then recieved erythromycin with is enzyme inhibitor. Mostly he developed AKI related to CNI toxicity
I will manage this case by
1) cyclosporine trough level to document the cause of AKI
2)Stop erythromycin and decrease cyclosporine targeting trough level around 100ng/ml
3)good hydration and stop ARBS if he was recieving.
4) ask for virology screen specially cmv pcr quantitative analysis
5) if no improvement rebiopsy as biopsy showed tubules and insufficient biopsy.
Describe the histology?
Just tubules shows isometric vacuolization most compatible with acute CNI toxicity.
What is the likely diagnosis?
Acute cyclosporine toxicity caused by enzyme inhibitor increased its trough level.
Describe the mechanism of injury?
Still unclear but maybe related to ischemic insult caused afferent v.c after dysfunction of vascular endothelial cells and decrease V.D like NO and increase V.C like angiotensin 2 or related to abnormal intracytoplasmic structures like retinaculum
This patient is a transplant recipient on Cyclosporine. Use of erythromycin, a CYP3A4 inducer can decrease metabolism of CNI, leading to elevated drug levels, leading to acute graft dysfunction, as in this case.
The management in this case would involve:
1) Ordering Cyclosporine drug level: which would be high
2) Stopping erythromycin.
3) Reducing the cyclosporine dose so that the cyclosporine level could be reduced. But keep a watch on the levels as once the effect of erythromycin wears off, the cyclosporine levels will go down and may become sub-therapeutic necessitating increase in cyclosporine dose again.
The renal biopsy would have been performed only if the CNI level was normal.
This graft biopsy shows tubular cells with vacuolar changes. Isometric vacuolization of tubular cytoplasm is the finding seen in acute CNI toxicity. This happens due to increased lysosomes and enlarged endoplasmic reticulum.
The diagnosis is acute CNI (cyclosporine) toxicity.
The mechanism of these tubular changes is due to relative ischemia caused by afferent arteriolar vasoconstriction. It is also thought to be due to direct effect of CNI on the structure and function of endoplasmic reticulum in tubular epithelial cells.
Reference:
Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508.
CNI induced tubular vacuolization.
This patient received erythromycin which is a Cp450 inhibitor, so the cyclosporine level in the blood is increased and this caused to acute kidney injury .
The biopsy shows isometric vacuolization of the tubules which is associated with acute cyclosporine nephrotoxicity.
High levels of cyclosporine leads to vasoconstriction of the renal vasculature through the activation of vasoconstrictors like renin angiotensin system and endothelin .
The isometric vacuolization in the tubular cells could result from relative ischemia due to vasoconstriction of the renal vasculature or could be due to direct effect of cyclosporine on the endoplasmic reticulum.
Erythromycin increases cyclosporine bioavailability about two-fold and decreases its clearance. So acute CNI toxicity in this case would be problematic.
Histology shows isometric vacuoles in proximal tubules. So, CNI toxicity diagnosis is most probable.
It is better not to use erythromycin in this case and prescribe other antibiotics that do not inhibit CYP3A4 for example azithromycin.
By EM, vacuoles are dilation of endoplasmic reticulum.
And is similar to osmotic nephrosis or contrast nephropathy. This acute toxicity is reversible by lowering the dose of cyclosporine
1. Liptak, P., Ivanyi, B. Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Rev Nephrol 2, 398–404 (2006).
Regarding the management I will either use another safe antibiotic with no effect on CNI or decrease CNI dose and it’s level monitoring.
The allograft biopsy is showing numerous tubules filled with uniformly-sized vacuoles in the cytoplasm, consistent with cyclosporine toxicity.
Cyclosporine level should be reduced and adjusted (level should be between 100- 125), and should thereafter be repeated in a period of 1-2 weeks to ensure that the dose is still within the therapeutic range.
The tubular vacuolization is potentially reversible and might not have a strong impact to the long-term graft outcome.
Mechanisms: Cyclosporine characteristic tubular vacuolization (TV) is an endoplasmic reticulum (ER) in origin. However, the cellular events of CsA-induced TV and CsA-induced ER remained unclear.
Cheng CH et al had shown that vacuolization occurred through CsA-induced ER stress and involved ER integrated stress response-related proteins (Bip/Grp78, ATF6, IRE1 and CHOP), in which Bip/Grp78 overexpressed on the membrane of TV and was essential for TV formation. Suppression of Bip/Grp78-enhanced CsA-induced cell death and CsA-induced TV formation and Bip/Grp78 overexpression had a characteristic striped pattern in the tubulointerstitium.
Reference
Cheng CH, Shu KH, Chang HR, Chou MC. Cyclosporine-induced tubular vacuolization: the role of Bip/Grp78. Nephron Exp Nephrol. 2012;122(1-2):1-12. doi: 10.1159/000346956. Epub 2013 Feb 15. PMID: 23428559.
• Would you manage this case differently?
Decrease the dose of cyclosporine and repeat serum drug level after 48 hr
•Describe the histology?
tubular vacuolization
•What is the likely diagnosis?
Acute CNI toxicity
Other causes of vaculation
mannitol and injection of radiographic contrast media.
PATHOGENESIS AND PATHOLOGY
Acute calcineurin inhibitor nephrotoxicity
cyclosporine causes vasoconstriction of the afferent and efferent glomerular arterioles and reductions in renal blood flow and glomerular filtration rate (GFR).
The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane).
. In addition, transforming growth factor (TGF)-beta-1, endothelin-1, and the production of reactive oxygen and nitrogen species have also been implicated
Kidney biopsy typically reveals an acute arteriolopathy and tubular vacuolization. Rarely, vascular lesions similar to those in the hemolytic uremic syndrome (HUS) are seen
The increase in vascular resistance may therefore be reflected clinically by an elevated plasma creatinine concentration and hypertension
Cyclosporine-induced renal vasoconstriction can cause delayed recovery from early AKI and, in severe cases, primary nonfunction. These complications are most likely to occur with prolonged ischemia time and high cyclosporine doses
however, even patients with therapeutic trough levels may show signs of nephrotoxicity.
Chronic calcineurin inhibitor nephrotoxicity
manifested by renal insufficiency due to glomerular and vascular disease, abnormalities in tubular function, and an increase in blood pressure
Kidney biopsy reveals an obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial fibrosis (producing a picture of “striped” fibrosis)
Reference
Update NOV.2021
I- Management :
This patient developed AKI after chest infection treated with erythromycin . management steps
1- Hospital admission
2- Assess volume status .
3- Check cyclosprin trough level
4- Revise all medication and stop erythromycin if the pt is still taking it.
5- Pelvi abd Us with duplex of graft vessels
6- Exclude other possible causes of acute graft injury in association with acute CMV pneumonia
II- the histology
No detected glomeruli , Tubules show cytoplasmic vaculation
III-The most likely diagnosis
Acute CNI toxicity.
IV – mechanism of injury
CNI causes reversible , dose-related vasoconstriction of the afferent glomerular arterioles and subsequent reductions in renal blood flow
Would you manage this case differently?
If I manage this case I will chose another type of AB not interfer with his IS.
Describe the histology?
Presence of isometric tubular vacuoles
What is the likely diagnosis?
Acute CNIs induced Nephrotoxicity
Describe the mechanism of injury?
Mechanism of CNIs injury
Acute CNIs Nephro toxicity is reversible due to vasoconstriction of afferent arterioles which is due to increase in vasoconstrictor factors like endothelin and thromboxan and activation of RAS, as well as reduction of vasodilator factors like prostacyclin ,prostaglandins E2 ,NO. and free radical formation
+ sympathetic nerve activation
+COX-2 inhibitor and associated decrease formation of prostaglandin E2 by calcineurin /NFAT inhibition could well be a major mechanism by which CNIs lead to renal vasoconstriction and decrease GFR.
Endothelin dysfunction is essential factor in the pathogenesis of acute CNIs nephrotoxicity
Tubular Effect
Isometric tubular vacuolization could be the consequence of relative ischemia caused by afferent arteriolar vasoconstriction
but the possibility that direct effect of calcineurin inhibitions in tubular epithelial cells cause alteration in endoplasmic reticulum structure and function can not be excluded.
TMA
endothelial injury secondary to vasoconstriction-associated ischemia , also increase platelet aggregation and activate prothrombotic factors .
Chronic CNIs Nephrotoxicity
Is irreversible damage of renal architecture
The etiology of chronic CNIs N has been studied extensively.A combination of cyclone-induced hemodynamics changes and direct toxic effect of cyclosporine on tubular epithelium is thought to play a role .
Vascular effect :
the underlying process and molecular mechanisms leading to smooth muscle cells changes are currently not elucidated, but may be related to the important function of calcineurin-NFAT in smooth muscle cells .
Tubulu-interstitial effect
1- local hypoxia or ischemia which lead to free radicals or reactive oxygen species production
2- upregulation of TGF-B
Also other mechanism is direct activation of apoptosis by CNIs
Reference:
Calcineurin Inhibitor Nephrotoxicity
Maarten Naesens, Dirk R. J. Kuypers and Minnie Sarwal
CJASN February 2009, 4 (2) 481-508; DOI: https://doi.org/10.2215/CJN.04800908
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation.
In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy
ACUTE CNI-INDUCED NEPHROTOXICITY
can take the form of functional toxicity, delayed recovery from post-transplantation acute tubular necrosis (ATN), toxic tubulopathy or vascular toxicity.
Functional toxicity
CNIs administered at pharmacological doses can cause vasoconstriction, a drop in glomerular filtration rate and elevation of serum creatinine level, in the absence of structural abnormalities in the biopsy specimen. This condition is most common in the early post-transplantation period.
Clinical correlation: functional toxicity is reversible in response to a lowering of the dose of the drug.
Delayed recovery from post-transplantation ATN
Prolonged warm or cold ischemia causes ATN in renal allografts, and manifests as oligoanuria in the immediate postoperative period. This condi- tion is a common complication of cadaveric renal transplantation. Morphological features include dilation and flattening of tubular profiles, loss of brush borders, necrosis of individual tubular epithelial cells, cytoplasmic basophilia and enlarged regenerative nuclei. Desquamation of tubular epithelial cells into the tubular lumen might be observed. Tubular changes are accompanied by interstitial edema and sparse lymphocytic infiltrates.Allografts with any degree of ATN are markedly sensitive to CNIs, which can prolong recovery from the ATN. Biopsy findings of CNI-induced nephrotoxicity are the same as those of post-transplantation ATN .
Clinical correlation: patients are maintained on dialysis until urine output has been restored and renal function recovered. Because of the potential for CNIs to exaggerate ischemic tubular damage, a drug of this class is introduced only when allograft function has been established.
Toxic tubulopathy
Patients with CNI-induced toxic tubulopathy present with acute allograft dysfunction, usually associated with an elevated serum drug level. Morphologically, isometric tubular vacuolation is observed focally, predominantly affecting the proximal straight tubules .The vacuoles are small, clear and evenly distributed throughout the cytoplasm. Ultrastructurally, the vacuoles correspond to dilations of the endoplasmic reticulum.Focal tubular calcification might also be present. The features of this type of tubulopathy are indistinguishable from those of radiocontrast nephrotoxicity and osmotic nephrosis, conditions to be considered when making the diagnosis.
Clinical correlation: toxic tubulopathy can be reversed by lowering the CNI dose.
Vascular toxicity
CNIs can have a direct toxic effect on endothelial cells, with or without the involvement of platelet aggregation. Two types of vascular toxicity have been identified, acute arteriolopathy and thrombotic microangiopathy.
Acute arteriolopathy
Patients present with acute allograft dysfunc- tion. The serum level of CNI is usually elevated. On biopsy, lesions are confined to afferent arte- riolar profiles. There is swelling and vacuola- tion of endothelial cells, vacuolation, necrosis and/or apoptosis and sometimes dropout of individual myocytes, and early replacement of damaged myocytes with rounded plasma protein insudates (hyalinization). Immuno- histochemically, the insudates are positive for IgM and C3. Acute arteriolopathy and toxic tubulopathy can co-exist.
Clinical correlation: the clinical outcome of CNI-induced acute arteriolopathy varies. Some patients recover renal function after the dose of CNI has been reduced, while in others renal damage is irreversible. In clinical practice, the diagnosis of arteriolopathy frequently leads to cessation of CNI administration.
Thrombotic microangiopathy
A rare manifestion of CNI-related vascular nephrotoxicity is a clinical picture resembling the hemolytic–uremic syndrome. Biopsy reveals thrombotic microangiopathy (TMA), character- ized by thrombi in the lumina of arterioles and glomerular capillaries .Pronounced arterial intimal changes are not typical of CNI- induced TMA. It is important to bear in mind, however, that CNI-induced TMA cannot be differ- entiated from other forms of TMA on the basis of morphology alone. The following possibilities should therefore be considered: acute humoral rejection (C4d positivity), bacterial or viral infec- tion, recurrent hemolytic–uremic syndrome, and anticardiolipin antibody-induced TMA.
Clinical correlation: diagnosis of CNI-induced TMA should prompt withdrawal of the drug because, if lesions are widespread and asso- ciated with extensive arterial mural necrosis and luminal thrombosis, graft loss develops.
Differential diagnosis
The main clinical conditions to be differentiated from acute CNI-induced nephrotoxicity are acute rejection, post-transplantation ATN and, on occasion, acute pyelonephritis.
CHRONIC CNI-INDUCED NEPHROTOXICITY
This form of CNI-related toxicity occurs several months after renal transplantation. Characterized by a slow, insidious increase in the serum creatinine level, patients usually have hypertension and sometimes moderate to nephrotic-range proteinuria. Some patients have an elevated serum level of ciclosporin or tacrolimus. The incidence of chronic CNI- induced nephrotoxicity increases with time since transplantation.The histological indicators of chronic CNI-induced nephrotoxicity are hyaline arteriolopathy, striped interstitial fibrosis and tubular atrophy.
Hyaline arteriolopathy
This lesion is the marker of chronic CNI- induced nephrotoxicity. It affects the afferent arterioles and distal portions of small inter- lobular arteries. Damaged smooth muscle cells are replaced by beaded hyaline deposits on the outer aspect of the media that bulge into the adventitia .Beaded medial hyalinosis is focal and can be over- looked as a result. In advanced cases, the entire wall is replaced by the hyaline material and the lumen is severely narrowed. Immunohistochemistry detects IgM and C3 at the sites of insudation. Staining is in a ‘pearl necklace’ pattern. Hyaline arteriolopathy must be differentiated from the arteriolar hyalinosis that is a feature of aging, hypertension and diabetes. In these three conditions, hyalinosis is primarily subendothelial and rarely extends into the adventitia, and necrosis of myocytes is not observed.
Interstitial fibrosis and tubular atrophy
In chronic CNI-induced nephrotoxicity, the interstitium shows prominent patchy fibrosis and corresponding tubular atrophy, with pref- erential and early involvement of the medul- lary rays. This results in a band-like pattern (Figure 5). This striped pattern is characteristic of, but not specific to, chronic CNI-induced nephrotoxicity; hypertensive kidney disease can produce a similar lesion.
Glomerular changes
The effects of chronic CNI-induced toxicity on glomeruli tend to be nonspecific. Compensatory glomerular hypertrophy, mesangial matrix expansion, capillary collapse, and focal segmental and/or focal global sclerosis can be observed.
Clinical correlation: chronic CNI-induced kidney damage is irreversible. Appropriate management is dose reduction or discontinua- tion of ciclosporin or tacrolimus, and admin- istration of alternative immunosuppressive agent.
Differential diagnosis
The main clinical conditions to be differentiated from chronic CNI-induced nephrotoxicity are chronic rejection/chronic allograft nephropathy (CAN), de novo or recurrent glomerulonephritis, and polyomavirus nephropathy.
References:
Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts
Peter Liptak et al. Nat Clin Pract Nephrol. 2006 Jul.
Calcineurin Inhibitor Nephrotoxicity
Maarten Naesens, Dirk R. J. Kuypers and Minnie Sarwal
CJASN February 2009, 4 (2) 481-508; DOI: https://doi.org/10.2215/CJN.04800908
This patient on cylcosporine therapy which interact with many drugs include erythromycin, which act as enzyme inhibiter lead to increase level of the drug causing toxicity and lead to sever vasoconstriction of the renal vasculature through the activation of vasoconstrictors like renin angiotensin system , endothelin and inhibition of vasodilators like NO , prostaglandin E2 , and prostacyclin causing ischemia.Diagnosis CNI toxicity
Biopsy showed Isometric vacuolization of proximal tubule and loss of bush border .Instead of erythromycin Iwill give azithromycin .
– We need to stop erythromycin immediately if it is still on
– Measure level of cyclosporin
– Check hydration status and may need IV fluid and monitor UOP and RFT
– Graft biopsy
– Dialysis if still rft deteriorating
**Administration of a calcium channel blocker can prevent the renal vasoconstriction, although not the rise in endothelin excretion. This observation constitutes part of the rationale for the use of calcium channel blockers to treat hypertension in cyclosporine-treated transplant recipients.
isometric vacuolization of the tubular cytoplasm, acute arteriolopathy
Acute cyclosporin toxicity
vasoconstriction of the afferent and efferent glomerular arterioles and reductions in renal blood flow and glomerular filtration rate (GFR). The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane). Increased sympathetic tone also may be present, although renal vasoconstriction occurs even in denervated kidneys. In addition, transforming growth factor (TGF)-beta-1, endothelin-1, and the production of reactive oxygen and nitrogen species have also been implicated
Dear All
Still, no one answered how vacuolation in acute CNI toxicity happened.
the exat mechanisim not fully understood but acute CNI toxicity can lead to dirct osmotic injury to the proximal tubuler cells with lysosomal swelling and mitochondrial toxicity which manifests with either isometric cytolasmic vacuolization or more rarely as giant mitochondria with abnormal cristae (dysmorphic), appearing as eosinophilic cytoplasmic inclusions in tubular epithelial cells on H&E and by EM , megamitochondria due to cytoplasmic swelling , also can be seen with antiretoviral medication like tenovir group.
reference:
CKJ REVIEW Acute kidney injury pathology and pathophysiology: a retrospective review Joseph P. Gaut and Helen Liapi
Clinical Kidney Journal, 2021, vol. 14, no. 2, 526–536
Seems to be: morphologic expression of arteriolar vasopsasm.
https://reader.elsevier.com/reader/sd/pii/S246802491730428X?token=5EFF31D8AA210AE03D64BA1579944B6E341F012DAA48013A335AE1A343B637144F0D14FA559B9211BD9FCC8BA8178156&originRegion=eu-west-1&originCreation=20211203185729
I would mange this case by stopping the erythromycin immediately because it is a one of macrolide antibiotics which cause CNI toxicity by inhibiting the enzyme CYP3A4 ,then reduce the dose of cyclosporine till target level. CNI toxicity include obliterative arteriolopathy/
hyalinization of the afferent arteriole, ischemic collapse or glomerular scarring, tubule vacuolization, focal and global segmental glomerulosclerosis, focal interstitial fibrosis associated with macrophage influx, and tubular atrophy .The main histological feature in this case is isometric tubular vacuolization . The diagnosis is acute CNI toxicity .
1 – the patient has chest infection and treated with erythromycin and he is on cyclosporine therapy
Erythromycin even in low doses may increase the calcineurin inhibitor level so increase its toxicity
and we should not give erythromycin to that patient
2 – the cells of tubules contain numerous uniform vacuoles
3 – acute cyclosporine nephrotoxicity
Would you manage this case differently?
Choice of antibiotics in renal transplantation patients must be with caution especially for drug drug interaction, dose adjustment with e GFR and nephrotoxicity .
I will choose any ather antibiotic than erythromycin as its enzymes inhibitor inhibit CYP3A4.and increases CNI level .
Its mostly reversible with dose reduction.9
Describe the histology?What is the likely diagnosis?
Light microscopy from a kidney allograft recipient with acute calcineurin inhibitor toxicity reveals arteriolar vacuolization;small clear cytoplasmic vacuolization referred to as “isometric vacuolization.
Acute CNI Toxicity
Acute CNI nephrotoxicity typically occurs early after kidney transplantation, correlates with the period of high CNI exposure, and is often reversible with dose reduction or discontinuation of the drug.
There are 3 major clinico-pathologic manifestations of acute CNI toxicity: functional/acute arteriolopathy, thrombotic microangiopathy (TMA), and toxic tubulopathy.
1 Acute arteriolopathy is a hemodynamically mediated phenomenon that leads to allograft dysfunction secondary to afferent arteriolar constriction and increased renal vascular resistance.Sometimes, acute arteriolar toxicity can manifest as arteriolar wall vacuolization, which is a morphologic expression of arteriolar vasospasm .
arteriolar wall vacuolization is neither sensitive nor specific for CNI toxicity and can be even encountered in a subgroup of implantation biopsies.
2 TMA is a rare manifestation of a more severe form of acute CNI-induced vascular damage. Extensive endothelial injury causes endothelial leaking, necrosis, or sloughing that consequently leads to antifibrinolysis, platelet aggregation, and activation of coagulation cascades.
Accordingly, the biopsy usually shows fibrinoid necrosis and/or thrombi affecting the afferent arterioles, and to a lesser extent, the glomeruli. The differential diagnosis of CNI-induced TMA should include other forms of TMA, such as accelerated antibody-mediated rejection, anti-phospholipid syndrome, procoagulant states, and recurrent hemolytic–uremic syndrome.Therefore, clinical correlation is highly important to obtain a precise diagnosis.
3 toxic tubulopathy. The most common histological finding is isometric cytoplasmic vacuolization of the proximal tubules, which is usually focal in nature. These vacuoles are composed of enlarged endoplasmic reticulum. As the name isometric implies, the vacuoles are small and evenly distributed within the cytoplasm In addition to the enlarged endoplasmic reticulum, the affected tubules can sometimes show giant mitochondria.
CNI-induced tubular toxicity may manifest morphologically as tubular degenerative changes without overt isometric vacuolization. In an early for cause allograft biopsy without concurrent rejection or other known causes of acute tubular necrosis (ATN), the possibility of acute CNI toxicity should be raised when observing a combination of acute tubular and vascular injury,
Rita Leal,Ibrahim Batal.Pathology of Calcineurin and Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation.Kidney International Reports.Volume 3, Issue 2, March 2018, Pages 281-290
For sure I would check the level of cyclosporin 2-3 days after starting the drug and modify dose
I could not understand the pathology but I guess there is mononuclear inflammation (tubulitis ???) ):
Would you manage this case differently?
Yes, I wouldn’t use erythromycin because it enzyme inhibitor that leads to increase level of cyclospoine which leads to CNI toxicity. I will use any other antibiotics that do not affect the CYP3A4 enzyme.
–Macrolide antibiotics classify into 3 groups based on data provided in vitro experiment:
1. Group 1 agents include erythromycin and troleandomycin. Both drugs bind strongly and inhibit CYP3A4.
2. Group 2 agent clarithromycin exhibits a low affinity for CYP3A4 as compared to erythromycin.
3. Group 3 include azithromycin and dirithromycin which interfere poorly with CYP3A4 .1
-I will stop cyclosporin and daily follow up to its level until reach its target and then reintroduce cyclosporine again.
2. Describe the histology?
Tubular vacuolization.
3. What is the likely diagnosis?
Acute CNI toxicity.
4. Describe the mechanism of injury?
-CNI acute nephrotoxicity can occur at any time post-transplantation and at any level of drug exposure but commonly with supratherapeutic trough levels.
-Acute CNI toxicity often presents with an increase in plasma creatinine concentration due to acute afferent arteriole vasoconstriction. However, vasoconstriction and increased allograft vascular resistance may occur before clinical evident 2.
-There is impairment of endothelial cell function resulting from decreased production of vasodilating prostaglandin E2 and nitric oxide and increase production of thromboxane and endothelin in afferent arterioles.3,4
-This can lead to an acute reduction in renal blood flow, which is reversible after CNI dose reduction or cessation.
-CNIs are also associated with acute development of de novo thrombotic microangiopathy (TMA) resulting in AKI, Haemolytic anemia, and thrombocytopenia.
References
1.Von Rosenstiel NA, Adam D. Macrolide antibacterials. Drug interactions of clinical significance. Drug Safety. 1995;13:105–122.
2.Curtis JJ, Luke RG, Dubovsky E, Diethelm AG, Whelchel JD, Jones P. Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet. 1986;2(8505): 477–479.
3. Lanese DM, Conger JD. Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles. J Clin Invest. 1993;91(5): 2144–2149.
4. De Nicola L, Thomson SC, Wead LM, Brown MR, Gabbai FB. Arginine feeding modifies cyclosporine nephrotoxicity in rats. J Clin Invest. 1993;92(4): 1859–1865.
Thank you all
Why do we have these vaculations in CNI toxicity? what is the mechanism of the vaculation?
Only few gave explantation
block of mitochondrial permeability pores by cyclosporin will lead to enlarged mitochondria seems vacuolated cells
-The endoplasmic reticulum (ER) stress and unfolded protein response (UPR), accompanied by a decrease in cyclophilin B (ER-resident PPlase) preceded the formation of vacuoles.
-Extensive vacuolated cells eventually undergo cell death which lacked the typical apoptotic features but showed a decrease in AIP (ALG2 interacting protein) as seen in paraptosis (non-apoptotic cell death).
Cyclosporine toxicity causes mitochondrial swelling
isometric vacuolization of the tubular cytoplasm, as a result of enlargement of the endoplasmic reticulum and increased lysosomes
1- Stopping Erythromycin.
2- Serial monitoring of serum Cyclosporin levels with adquate dose adjustment.
one or more dose missing may be needed.
3- Control of BP and other hemodynamics.
4- Serial follow up of urine output and renal chemistry.
1- tubualr vacculation.
2- mesangial proliferation and mesangiolysis.
3- vascular arteriolopathy.
acute graft dysfunction due to acute CNI toxicity caused by HME inhibition by Erythromycin
tubular and vascular injury caused by VC, RAS activation, direct cell injury ….
Would you manage this case differently?
I would prescribe Azithromycin as it differs from Erythromycin in that it doesn’t inhibit CYP3A4 and is not associated with changes in CNI metabolism (1)
Cyclosporine peak level C2
Describe the histology?
Isometric vacuolation of tubular cytoplasm
What is the likely diagnosis?
Acute CNI nephrotoxicity due to co-prescription of cyclosporine and erythromycin
Describe the mechanism of injury?
Decreased production of vasodilators (prostaglandin E2 and nitric oxide) with increased production of vasoconstrictors (Thromboxane A2 and endothelin) in the afferent arteriole leads to significant impairment of endothelial cell function (2)
this leads to acute reduction in renal blood flow which is reversible after dose reduction or drug cessation. (3)
(1). Fleet JL, Shariff SZ, Bailey DG, et al. Comparing two types of macrolide antibiotics for the purpose of assessing population based drug interactions. BMJ Open. 2013;3(7):1-7.
(2) De Nicola L, Thomson SC, Wead LM, Brown MR, Gabbai FB. Arginine feeding modifies cyclosporine nephrotoxicity in rats. J Clin Invest. 1993;92(4):1859-1865.
(3) Farouk, Samira S., and Joshua L. Rein. “The many faces of calcineurin inhibitor toxicity—what the FK?.” Advances in chronic kidney disease 27.1 (2020): 56-66.
Would you mange this case differently?
It is very important to recognize certain drugs that potentiate CNIs nephrotoxicity . It is better to use drugs with least interaction with CNI. When there is a clinical indication to use drugs ,that interact with CNI ,it is better to withholding of concomitant drugs ( ACE ,ARBs ,NSAIDs) with close monitoring of CNI level and kidney function .
Erythromycin induce acute CNI toxicity in this patient can be managed with;
-with holding erythromycin ( the offending agent ) , as no further clinical indication .
– with holding of CNI with close monitoring of its level and resume immediately ,if the level is allowable.
-with holding of any concomitant drugs ,that can potentiate nephrotoxicity .
-ensure well hydration .
Describe the histology;
isometric vacuolization of the proximal tubule and loss of brush borders.
What is likely diagnosis?
Acute CNI toxicity.
Describe the mechanism of injury?
CNI causes two type of vascular injury ( acute arteriolopathy and TMA) leading to tubular ischemia and tubular injury .
Can CNI toxicity happen with evidence of cell-mediated rejection if yes ,what is the mechanism?
Yes
Acute CNI toxicity causes vascular injury in form of arteriolopathy or TMA ,which is resemble acute rejection . there is reported case of concomitant TMA and AMR ( AMR associated TMA).
What are the other causes of vaculation?
Isometric tubular vacuolization in addition to CNI toxicity is described after administration of mannitol , injection of radiographic contrast and low dose of intravenous immunoglobulin.
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
Acute CNI toxicity is characterized by areriolopathy and tubular vacuolization . while Chronic CNI toxicity is characterized by interstitial fibrosis (striped fibrosis) , tubular atrophy, and hyaline deposits in the arterioles (nodular arterial hyalinosis) .
Reference;
Drachenberg C, Papadimitriou JC. Practical renal allograft pathology. In Weir MR, Lerm EV (eds).
Kidney Transplantation. Practical Guide to Management. New York, Springer, 2014, pp 355–375.
Fogo A. Fundamentals of Renal Pathology. New York, Springer, 2014, pp 1–230
– Erythromycin can inhibit the metabolism of cyclosporine by binding to CYP3A4. Increasing the cyclosporine level while azithromycin is a macrolide that is used for similar indications as erythromycin, but differs in that it does not inhibit CYP3A4 and is not associated with changes in cyclosporine metabolism.So erythromycin need to be stopped and cyclosporine level checked and dose reduced .
-Acute CNI toxicity is showing in the biopsy vacuolation of the proximal tubules.
Histologically, acute CNI hemodynamic effects are associated with any morphologic lesions.
– Cyclosporine induce vasoconstriction of the afferent arteriole by causing an imbalance between vasoconstrictor agents and activation of the renin-angiotensin system and decrease of vasodilator factors.The arteriolar vasoconstriction induces an acute reversible impairment of renal function and also acute reversible tubular dysfunction. This vasoconstriction is dose-dependent and is reversible
– chronic CNI nephrotoxicity is a major cause for renal allograft failure based on histological lesions that were specific for cyclosporine nephrotoxicity such as striped interstitial fibrosis, arteriolar hyalinosis, tubular atrophy, and glomerulosclerosis).
Issa N, Kukla A ,Ibrahim H.N. Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence .Am J Nephrol 2013;37:602-612
radiocontrast nephrotoxicity, intravenous immunoglobulins , and osmotic nephrosis(including solutions of mannitol, inulin, glucose, sucrose, dextran, hydroxyethylstarch, urea, and radiocontrast agents))
2.Is acute CNI toxicity has different pattern from chronic CNI toxicity?
acute CNI nephrotoxicity :
chronic CNI nephrotoxicity :
3.Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
I suppose from the phrasing of the question that the answer is yes , despite the fact that CNI toxicity and rejection represent the two extreme ends of a spectrum.
i will guess, if that is allowed, because i did not find any data on the subject. i think the coexistence of histological pattern of both CNI toxicity and cellular rejection might occur in cases of subclinical cellular rejection , not on treatment, when they have high CNI level all of a sudden either secondary to rapid increase in doses or food/drug interaction.
this also may occur in patients with fluctuating compliance with skipping doses and getting the double dosing. Another suggestion is that secondary to graft ischemia in CNI toxicity ,some antigens are exposed after cells apoptosis, so with omission of doses ,T cells may recover from the suppressing effect of CNI.
The response to Question 3 ”Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?” needs to be reformated. Answering should be based on evidence Not guessing
– Acute kidney damage from erythromycin, a recognized cyclosporine inducer that inhibits cytochrome P450.
-A tubular vacuolization appear in the renal biopsy.
-Acute CNI toxicity can cause afferent arteriolar vasoconstriction, which is reversible.
when using one of the enzymes inhibitors, we reduce the CNI dose by 40%.
-we recommend stopping erythromycin(azithromycin lesser effect on CNI).and reducing the dose of cyclosporin by 40 to 50%.
I would have managed his chest infection with beta lactam antibiotic like amoxicillin, or any medication that will not affect the level of cyclosporine .
the histology revealed isometric vacuolation of renal tubules ,suggesting CNI toxicity as a diagnosis . the mechanism of injury involve dilatation of endoplasmic reticulum.
ref: Liptak, P., & Ivanyi, B. (2006). Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts. Nature Clinical Practice Nephrology, 2(7), 398–404. doi:10.1038/ncpneph0225
This is a case of CNI toxicity
Clues
1- Acute kidney injury following administration of erythromycin which is a known drug that increase cyclosporine level as it inhibit cytochrome P450.
2- Renal biopsy showing tubular vacuolization and no evidence of TCMR, ABMR and TMA ( typical for CNI toxicity)
Mechanism of injury
CNI produce afferent and efferent arteriolar vasoconstriction may be due to endothelial cell dysfunction with decreased production of vasodilators (prostaglandins and nitric oxide) and increased production of vasoconstrictors (endothelin and thromboxane) leading to tubular ischemia and tubular injury, more over CNI increase oxidative stress with production of ROS thus adding to injury.
Management
1. Order cyclosporine level
2. Stop erythromycin and decrease the dose of cyclosporine keeping the level between 50-150 and follow up creatinine level. AKI related to CNI toxicity is usually reversible once the drug dose is reduced since this effect is dose related
3. Adjust hydration state
4. Hold ARBS temporary if used, consider switch to amlodipine if no significant proteinuria as CCB was found to decrease the nephrotoxic effect of CNI
5. Monitoring of electrolytes and blood gas is recommended since there is increased incidence of hyperkalemia and RTA -4
Excellent
this common scenario in transplant clinc ,
CNIS are very sensitive to enzyme inducers and inhibitors of cytochrome p450 in liver,and inteistine.
cnis are metblized by cytochrome p450, so any drug will chnage the activity of cytochrome p450 will make adifference in their levels in the blood .
some drugs inhibit the action of cytochrome p450 making their levels high and other will induce them cause their level to be low .
the section showed above showing vacuolization of the cells with disrupted membrane.
in our case , erthromycin is a potent enzyme inhibitor , so it wll increas its bioavialbity , leading to increase his level in blood, causing nephtotoxity, due to cute arteriolopathy which is related to acute arteriole vasoconstriction, mainly the afferent arterioles.
In general CNI related renal toxicity is thought to be induced by several factors, resulting from a combination of an increase in vasoconstrictive factors (endothelin and thromboxane), activation RAAS, decrease in vasodilator factors (nitric oxide (NO) and prostacycline).
i will stop erthyromycin , and shift the pt to any anibiotic which dosent interfer with cytochrome p450.and hold cyclosporine with close monitor of daily level by c2 til reaches desired level then i will introduce it again with the same dose.
Excellent
why C2 level ? is their any prefernce in this case ?
Yes I will manage differently , stop erythromycin and replace by azithromycin for 3-6 days , and decrease dose of cyclosporine with close monitoring of trough level C0 or C2, or replace cyclosporine by tacrolimus in ratio 50:1 mg per day. Offer good hydration.
The histology shows vacuolization of the cells with disrupted membrane.
Diagnosis is acute kidney injury due to cyclosporine nephrotoxicity.
Mechanism of injury: erythromycin increase absorption of cyclosporine and decrease its metabolism.
Metabolism of cyclosporine is through cytochrome P450 IIIA enzyme in the liver and intestine, it will converts cyclosporine to its metabolites, erythromycin compete with cyclosporine on cytochrome P450 IIIA (erythromycin inhibit CP450), so leads to increase its bioavailability by 2 folds, increase its toxicity. So, should not be given in renal allograft recipient receiving cyclosporine.
Cyclosporine induce oxidative stress which has a major role in the pathogenesis of cyclosporine nephrotoxicity, it induce ER (endoplasmic reticulum) stress, and increase ROS (reactive oxidative stress) produced by mitochondria, decrease nitric oxide NO synthesis and leads to afferent arteriolar vasoconstriction.
Anne M. Baciewicz , Frank A. Baciewicz Jr. Cyclosporine pharmacokinetic drug interactions. The American Journal Of Surgery. 1989 vol.157, P264-71.
Qinghua Wu , Xu Wang , Eugenie Nepovimova , Yun Wang , Hualin Yang , Kamil Kuca. Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signaling.
Food Chem Toxicol. 2018 Aug;118: 889-907
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Well done
The presented case describes acute renal allograft injury on top of chronic allograft nephropathy as it seems with rising of serum creatinine more than 20% of the baseline serum creatinine.
Basically we have to make a differential diagnosis based on the data available:
1-We have rising of serum creatinine and decrease UOP (acute allograft injury)
2- We have suspicion of CNI toxicity as per scenario of using hepatic enzyme inhibitor erythromycin that can increase the level of cyclosporine to renal toxic level causing allograft injury
3-Based on a renal histopathology slide showing:
-Section of only tubules ,no glomeruli
-Stained with H& E stain, LM, high power
-Findings of tubular isometric vacuolization (uniformly-sized vacuoles in the tubular epithelial cytoplasm)
-causes of tubular isometric vacuolization in renal allograft :
* Acute CNI (Tacrolimus or cyclosporine) toxicity with with high CNI levels.
*We have to exclude de nofo Thrombotic microangiopathy (TMA) related to antibody mediated rejection and usually showing significant microvascular inflammation and peritubular capillary C4d staining and the patient has donor-specific antibodies.
*Exclude history of Intravenous immunoglobulin infusion
*Rule out other possible causes of TMA, including HUS/TTP, malignant hypertension, recurrent disease , and antiphospholipid antibody syndrome
The most likely diagnosis after excluding other etiologies is acute CNI toxicity
-Mechanism of acute CNI toxicity :
There are 3 major clinico-pathologic manifestations of acute CNI toxicity:
a-Acute arteriolopathy is a hemodynamically mediated leads to allograft dysfunction secondary to afferent arteriolar vasoconstriction and increased renal vascular resistance
Sometimes, acute arteriolar toxicity can manifest as arteriolar wall vacuolization, which is a reflection of arteriolar vasospasm.
b-TMA is the manifestation of severe form of acute CNI induced vascular damage, biopsy usually shows fibrinoid necrosis and thrombi affecting the afferent arterioles.
c-Direct toxic tubulopathy and the most common histological finding is isometric cytoplasmic vacuolization of the proximal tubules, which is usually focal in nature.
The management of acute CNI toxicity to hold or reduce the CNI dose and follow up graft function with monitoring of CNI level.
References:
B. Murray, M. Paller, T. Ferris: Effect of cyclosporine administration on renal hemodynamics in conscious rats Kidney Int, 28 (1985), pp. 767-774
C. Ponticelli :De novo thrombotic microangiopathy. An underrated complication of renal transplantation Clin Nephrol, 67 (2007), pp. 335-340
I can see your hard work. Well done
Oral absorption of cyclosporine variable & inter patient variability may be due to its metabolism donor by cytochrome P450( CYP3A4) & bioavailability affected by intestinal absorption. So any medication interferes with this cytochrome can affect the metabolism of cyclosporine.
Drugs inhibit cytochrome P450 ( increase cyclosporine ) e.g.
Drugs induce cytochrome P450( decrease cyclosporine ):
The patient treated with erythromycin which inhibit cytochrome P450 leading increase cyclosporine level causing acute kidney injury. This antibiotic should be stopped & decreasing the dose of cyclosporine may be needed with close monitoring of drug level. Acute kidney injury confirmed by renal biopsy that show isometric tubular vacuolization ( LM shows section of renal tubules stained with PAS stain & diffuse isometric tubular vacuoles). Isometric tubular vacuolization may be due to ischemia that result from afferent arterial vasoconstriction & due to direct CNI effect on tubular epithelial cells that causing changes in endoplasmic reticular structure & function.
References:
Well done
Excellent
This patient had kidney transplantation before 3 years on triple immunosuppressive drugs including cyclosporine , received erythromycin which is known as an inhibitor of enzyme, so the cyclosporine level in the blood is increased and this leads to acute kidney injury .
Cyclosporine had narrow therapeutic window so drug level monitoring is necessary , also we should know the drug drug interaction , and to use the drugs that less likely to affect the metabolism of this drug, or if we use the drugs that affect the metabolism of cyclosporine , we should monitor the cyclosporine blood level more closely. For this patient if the use Azithromycin instead of erythromycin will be better to avoid this complication.
The biopsy show isometric vacuolization of the tubules which is associated with acute cyclosporine nephrotoxicity.
High blood level of cyclosporine leads to sever vasoconstriction of the renal vasculature through the activation of vasoconstrictors like renin angiotensin system , endothelin and inhibition of vasodilators like NO , prostaglandin E2 , and prostacyclin.
The isometric vacuolization in the the tubular cells due to enlarged endoplasmic reticulum and lysosomes could result from relative ischemia due to sever vasoconstriction of the renal vasculature or could be due to direct effect of cyclosporine on the endoplasmic reticulum.
Well done, References?
Management Plan
Histology showed vacuolation of the proximal tubules; sign of CNI toxicity.
Diagnosis : CNI Toxicity precipitated by the use of macrolide (Erythromycine).
Mechanism of Injury
Cyclosporine (CsA) is the current primary immunosuppressant for the prevention of allograft rejection in solid organ transplantation. However, owing to its molecular mechanism of action the drug is associated with various adverse side effects (eg, nephrotoxicity). Histological changes appear as obliterative vasculopathy of the afferent arteriole and tubulointerstitial fibrosis in advanced cases. The underlying pathomechanisms of this condition reflect an altered release of vasoactive substances, such as angiotensin II, endothelin, prostaglandins, and nitric oxide as well as the stimulation of proliferative genes such as transforming growth factor-beta, osteopontin, and collagen I and IV.
The elevation in serum Cr in this patient is because of acute CNI nephrotoxicity. Cyclosporin level has been increased after treatment with erythromycin. Erythromycin, even in low doses, may increase CNI levels. It is a moderate CYP3A inhibitor. Other macrolide antibiotics (clarithromycin, josamycin, ponsinomycin) may also increase CNI levels. There are conflicting reports about the impact of azithromycin on drug levels. This drug can be given in a short course without monitoring. So, if the patient needed macrolide therapy for possible pneumonia infection, azithromycin would been a better choice or cyclosporin level had to be monitored after the initiation of treatment with erythromycin. Acute cyclosporin nephrotoxicity is a result of dose dependent, reversible vasoconstriction.
The probable mechanism of vasoconstriction is substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostacyclin and NO) and enhanced release of vasoconstrictors (endothelin and thromboxane), as well as increased sympathetic tone and NOS inhibition. Vasoconstriction may be more pronounced with cyclosporine than with tacrolimus.
This figure illustrates relative luminal dilation and epithelial cell flattening of tubules accompanied by more specific finding means tubular vacuolization with small isometric vacuoles in tubular cell cytoplasm.
Vacuolization is most prominent in the S3 segment of the proximal tubule and is more common with higher drug levels.
Description of the histology:
The proximal tubules show loss of brush borders and isometric clear vacuolization (defined as cells filled with uniformly sized vacuoles)
what is the likely diagnosis?
This is patient is taking a CNI – cyclosporine, as part of the maintenance immunosuppressive therapy. Cyclosporine is metabolized in the liver and intestine by means of CYP450 enzymes, mainly CYP3A4.
In the other hand, some other drugs are considered a potent CYP450 inhibitors like erythromycin, clarithromycin, azoles, verapamil and grapefruit and others.
In our clinical scenario the patient is on cyclosporine and received a 7 day course of erythromycin, so due to erthyromycin inhibition of CYP3A4, it is expected to have a high levels of cyclosporine in the blood and eventually major side effects. Renal adverse events at histological level can be related to tubules-tubulopathy, arterioles-arteriolopathy or thrombotic microangiopathy.
The histology provided in the clinical scenario is in compatible with tubular injury manifested ad proximal tubules vacuolization which is typical for CNI renal toxicity.
Would you manage this case differently?
When treating patient with kidney transplantation, we should always remember the possible drug-drug interaction, especially that patients are polymedicated.
So antibiotic of choice would be the one with no or minimal effect on immunosuppressive drug metabolism. Azithromycin, for instance does not inhibit CYP450 and can be used safely.
Describe the mechanism of injury
nephrotoxicity due to calcineurin inhibitor toxicity is due to acute arteriolopathy which is related to acute arteriole vasoconstriction, mainly the afferent arterioles.
In general CNI related renal toxicity is thought to be induced by several factors, resulting from a combination of an increase in vasoconstrictive factors (endothelin and thromboxane), activation RAAS, decrease in vasodilator factors (nitric oxide (NO) and prostacycline), and formation of free radicals.
Well done.
References?
the LM of graft biopsy shows the typical acute kideny injury with slough and swelling with isometric voculations ,no tubulitis , its acute tubular necrosis , based on the history given likley its due to acute CNI toxicity due to the interaction with the recently prescribed azithromycin antibiotic for the treatment of chest infection
CNI nephrotxicity can be enhanced with concumtitant use of drugs that inhibit cytochrom p450 and erthromycin is one of the macrolide AB even in low dose can increase the cyclosprine level,
need to check the cyclosprine trough level with close monitroing of the graft function ,and to consider the dose adjustment of cyclosorine with such combination usually will reduce the dose of cyclsoprine during the course duration of AB the first 1-2 week .
acute CNI nephrotoxicity its dose related reversible renal vascoconstriction that affect the afferent aerterioles its pre renal dysfunction in earlier stage then lead to ATN
references:
1- up to date medicine kidenytransplantaion in adults ;evaluation and diagosis of acute kidney allograft dysfunction .
2- handbook of kidney transplantaion , Fifith edition .
Acute tubular injury resulting from acute CNI toxicity caused by the use of erythromycin as this drug is well known to increase CNI level through inhibition of CYP3A. management consist of stopping erythromycin, monitoring of CNI level & CNI dose reduction. the mechanism of injury is through afferent arteriolar vasoconstriction, also there is significant impairment of endothelial function resulting from decreased production of vasodilators such as prostaglandin E2 & nitric oxide, and increase production of vasoconstricting thromboxane and endothelin in the afferent arteriole leading to decrease blood flow which is reversible by CNI dose reduction or stopping the drug.
Histology:
acute tubular injury with isometric vacuolization
Can CNI toxicity happen with histological evidence of cell-mediated rejection? if yes, what is the mechanism?
could not find
What are the other causes of vaculation?
1)seen in allograft biopsies of patients maintained only on steroids and azathioprine
2)clinical settings such as renal ischemia or tubular epithelial injury caused by intravenous administration of hyperosmotic fluids (e.g., including solutions of mannitol, inulin, glucose, sucrose, dextran, hydroxyethyl starch, urea, and radiocontrast agents)
3) intravenous immunoglobulins can also cause vacuolization of tubular epithelial cells
Is acute CNI toxicity has different pattern from chronic CNI toxicity?
There are 3 major clinico-pathologic manifestations of acute CNI toxicity
functional/acute arteriolopathy
thrombotic microangiopathy (TMA)
toxic tubulopathy(isometric vacuoles)
The histologic indicators of chronic CNI nephrotoxicity
hyaline arteriolopathy(nodules)
striped tubulointerstitial scarring
glomerulosclerosis
Would you manage this case differently?
use antiobiotics such as cefixime and azithromycin/levofloxacin instead of erythromycin as it inhibits CYP3A4 and leads to increase in levels of cyclosporine leading to acute cyclosporine nephrotoxicity.
Describe the histology?
isometric vacuoles seen
What is the likely diagnosis?
acute cyclosporine toxicity
Describe the mechanism of injury?
dose related vasoconstriction in the afferent arteriole-reversible decrease in GFR
Calcineurin Inhibitor NephrotoxicityMaarten Naesens
AKI due to CNI toxicity after using erythromycin that inhibits cytochrome P450 leading to increase level of cyclosporine may use Azithromycin instead of erythromycin
describe the lesion :
-A tubular vacuolization appear in the renal biopsy.
Mechanism :
-Acute CNI toxicity can cause afferent arteriolar vasoconstriction, which is reversible. Due to endothelial dysfunction and decrease vasodilators .
treatment
it’s reversible
stop erythromycin
use other antibiotics as Azithromycin