1. A 31-year-old male received a kidney transplant from his brother 7 years ago, 111 mismatch, no pre transplant DSA, primary function. He had basiliximab induction; Tacrolimus based triple immunosuppression as maintenance. S Cr was stuck at 200 µmol/L. Both DSA and C4d were negative post-transplantation. See the biopsy below:
- Describe the significant features of the biopsy?
- Any more tests required to confirm your diagnosis?
- What is your management plan?
Slide A vacuolations
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
Please support your answer with a pathology slide (reference the source)
Slide B showed stripped interstitial fibrosis.
What is meant by stripped interstitial fibrosis?
What are the other causes of this condition?
Please support your answer with a pathology slide (reference the source)
What are the characteristics of CNI induced vacuolations
It is isometric vacuolization (nearly equal sized small vacuoles) in proximal tubular epithelial cytoplasm.fig(1) 1
and how they are different from the vacuolations caused by other conditions?Please support your answer with a pathology slide (reference the source)
Isometric tubular vacuolization can be due to osmotic nephrosis induced by administration of mannitol, glucose, sucrose, radio contrast agents, intravenous immunoglobulins.
Those can be differentiated histologically through electron microscopy, which will reveal dilated endoplasmic reticulum in CNI toxicity associated vacuolization. In ischemic tubular vacuolization, vacuoles are variable in size and the regenerating-type epithelium shows brush border flattening with blebbing.fig(2)2
What is meant by stripped interstitial fibrosis?
This appears as bands of TA/IF surrounded by areas of intact tubule-interstitium and shows an abrupt transition between the fibrotic and intact areas.fig(3)
What are the other causes of this condition? Please support your answer with a pathology slide (reference the source
1- chronic antibody-mediated rejection
2- chronic pyelonephritis or
3- reflux nephropathy with characteristic jigsaw pattern
4- scarring;
5- viral infection
6- diabetic kidney disease
7- crystals (eg, calcium phosphate )
8- recurrence of disease or de novo injuries.3
1- Liptak, Peter; Ivanyi, Bela (2006). Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts. Nature Clinical Practice Nephrology, 2(7), 398–404. doi:10.1038/ncpneph0225
2- 2- Fogo, Agnes B.; Lusco, Mark A.; Najafian, Behzad; Alpers, Charles E. (2017). AJKD Atlas of Renal Pathology: Osmotic Tubular Injury. American Journal of Kidney Diseases, 69(2), e11–e12. doi:10.1053/j.ajkd.2016.12.003
3- Fogo, Agnes B.; Lusco, Mark A.; Najafian, Behzad; Alpers, Charles E. (2017). AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. American Journal of Kidney Diseases, 69(5), e23–e24. doi:10.1053/j.ajkd.2017.02.002
Good
fig 1
isometric vacules
EM of vacules of other dd
IFTA
Characteristics of CNI induced vacuolations
Isometric cytoplasmic vacuolization of the proximal tubules, which are focal in nature. The vacuoles are made of enlarged endoplasmic reticulum. The affected tubules sometimes show giant mitochondria.
CNI induced tubular toxicity may manifest morphologically as tubular degenerative changes without overt isometric vacuolization. The possibility of acute CNI toxicity can be considered when there is a combination of acute tubular and vascular injury such as tubular degenerative changes and prominent arteriolar vacuolization or endothelial swelling.
TMA, a rare form of acute CNI induced vascular damage, can reveal endothelial injury in the form of fibrinoid necrosis, thrombi affecting afferent arterioles and glomeruli on biopsy.
Ref: Kidney International Reports, 2018
The above picture shows Acute CNI toxicity revealing isometric tubular vacuolization in the biopsy of the patient.
Other conditions
Tubular vacuolization can be seen in other conditions too but in contrast to the isometric vacuolization seen in CNI toxicity, the vacuoles in conditions like osmotic nephrosis are made of lysosomes that contain that culprit agent that enters cytoplasm via pinocytosis. There is also more pronounced swelling of tubular cytoplasm in osmotic nephrosis. This condition can occur after treatment with IVIG, dextran or administration of radio contrast.
References :
Striped interstitial fibrosis
Striped fibrosis refers to linear bands of interstitial fibrosis with atrophy of entrapped tubules. The striped appearance is because of areas of ischemic tubular atrophy and interstitial fibrosis alternating with well preserved or even hypertrophic rental tubules.
The underlying cause could be drug induced thickening and hyalinization of arterioles running parallel to each other in the cortex. With progressive narrowing, a linear zone of renal parenchyma is deprived of its nutrition and shows degenerative changes.
A direct effect of the drugs on the cortical medulla and inner medullary stripes is also possible.
Mechanisms involved that lead to interstitial fibrosis and tubular atrophy are :
Ref: PubMed Central, 2014
The figure above demonstrates the various mechanisms involved in interstitial fibrosis and tubular atrophy following kidney transplant.
Causes
Ref: Transplantation, 1999
This slide shows striped interstitial fibrosis.
References
Excellent very good choice of slides.
As regard isometric vaculization , it means equal sized vacules which are initially small then enlarge in size as extent, it can occur in:
a- CNI acute toxicity.
b. osmolar injury if renal tubules by infusion of highly osmotic substances as sucrose containing IvIg, starch especially in those dehydrated or using diureticsor have underlying CKD or use of hyperosomolar contrast.
_ ischemic ATN …cause renal tubular vaculization but not isometric
To differentiate between them:
First of all the history will be highly informative about causative agent, in addition to histopathological features.
a. CNI induced and osmotic injury can not be differentiated by LM , only by EM as CNI induced has dilated endoplasmic reticulum while in osmotic injury is dilated lysosomes ( early empty clear then full of lamellar or amorphous material).
b. CNI is focal affection with surrounding normal tubules
c. Both have preserved tubular epithelial brush border by EM
_ While ischemic ATN is characterized by loss of brush border and has variable sized vacules.
As regard stripped interstitial fibrosis:
It means linear ares of interstitial fibrosis and tubular atrophy which is surrounded by normal tissues.
The rationale behind this is arterial hyalinosis and subsequent ischemic changes in tubules and interstitium at the watershed area ( lies at the junction between 2 arteries) .
_ it can occur with many causes and again history will be helpful.
a. CNI toxicity .
b_ chronic AMR characterized by double contour of glomerular BM apparent in HX and EX and better with silver stain, plus multilayering of Ptc basement membrane more than 7 layers in addition to postive c4 d deposition in Ptc, in addition it is usually diffuse process unlike CNI induced, with glomerulsclerosis and marked intimal proliferation and medial hypertrophy ..EM here of sclerotic glomeruli shows effacement of foot process .
c_ hypertensive arteriosclerosis with subsequent IFTA ( characterized by duplication and multilayering of elastic lamina in arterioles).
d. Chronic pyelonephritis ( history of fever, loin pain, urinalysis pus cells, also US dilated renal pelvis with echoes inside, neutrophils infiltration in pathology).
_ we should exclude all these causes before considering IFTA as normal aging of the graft or previously known as CAN.
Isometric vaculaizatio
And here in attached photo of Em show preserved brush border
Here is duplication of elastic lamina in hypertensive arteriosclerosis, not present in CNI induced IFTA
Here is glomrular affection ( double contour of glomerular BM by HX and silver in transplant glomerulopathy, not present in CNI induced nephrotoxicity
Good effort. May I suggest this article for your review? https://www.ajkd.org/action/showPdf?pii=S0272-6386%2817%2930141-5
Thanks dear professor, I will read it
Excellent Mai but notice by chosen slides that vaculation can be seen by HE it is the brush border and further details that need EM.
yes, dear professor.
Fogo, Agnes B.; Lusco, Mark A.; Najafian, Behzad; Alpers, Charles E. (2017). AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. American Journal of Kidney Diseases, 69(5), e23–e24. doi:10.1053/j.ajkd.2017.02.002
stripped fibrosis
Concise but fine
Thnx prof
-Acute CNI toxicity is presented histologically by necrosis and early hyalinosis of smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal tubules,TMA is a rare manifestation for acute CNI toxicity.
Chronic CNI toxicity, the smooth muscle cells in the media of afferent arterioles are replaced by hyaline deposits .The interstitial tissues replaced by striped fibrosis and tubular atrophy.
Usually the incidence of acute CNI toxicity decreased markedly due to regular monitoring of CNI levels. In the other side Chronic toxicity still common and causes chronic allograft damage.
–characteristics of CNI induced vacuolations:
It is isometric (equal in size) proximal tubular epithelial cells vacuolations characterized by dilated endoplasmic reticulum and large lysosomes.
-Other causes of tubular vacuolations are :
1-IVIG administration
2-osmotic tubular injury by mannitol
3-ischemic acute tubular injury
4- tubular injury associated with lipiduria in nephrotic syndrome.
-stripped interstitial fibrosis:
Stripped interstitial fibrosis means fibrosis extending along the medullary rays caused by pronounced ischemia (caused by vasoconstrictive effect of CNI)and fibrosis happened in these anatomical areas. Another justification for stripped fibrosis is ischemic tubular atrophy and interstitial fibrosis alternating with relatively well preserved or even hypertrophic renal tubules.
Referrence
Dell’ Antonio G and Randhawa PS Striped pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimusTransplantation 1999;67:484-486
A-CNI induced Vacuolations
B-stripped fibrosis
Please notice that ivIg commonly used in transplant practice are innocent from causing toxic vaculation it is the Vector as MANITOL and SUCROSE are the cause eg. Sucrose nephropathy
This is rare now as iv Igs are mounted on safe vectors
vacuolation of proximal tubular epithelial cells can be induced by various kinds of mechanisms such as ischemia(CNI induced), hypokalemia, hyperosmolarity(mannitol and other) and lipid accumulation some case report also with SGLT2 inhibitor treatment for obese individuals can result in the damage of proximal tubules due to an overdose lavage of sugar into the urine(1).
CNI vacuolations is isometric (small and equal in size) other causes macrovaculation large in size and variable.(figure1)(1).
Stripped pattern fibrosis mean that fibrosis is in band and in between normal interstitial
A linear band of tubular atrophy is probably secondary to the arteriolar and interlobular (calcineurin inhibitor hypertension) lesions.
If two vessels become narrowed due to intimal sclerosis, we would expect a narrow area of renal parenchyma in the watershed zone to become atrophic, while the tissue in immediate proximity to the vessels will retain a reasonable blood flow; this would result in a striped pattern of fibrosis.
But also CNI may led to diffuse pattern (may be a later stage of the striped pattern of injury) (2)
Siroliums may increase CNI toxicity and increase pattern of fibrosis.
References:
1-Watanabe, S., Sawa, N., Mizuno, H. et al. Development of osmotic vacuolization of proximal tubular epithelial cells following treatment with sodium-glucose transport protein 2 inhibitors in type II diabetes mellitus patients-3 case reports. CEN Case Rep 10, 563–569 (2021). https://doi.org/10.1007/s13730-021-00609-7.
2-Presentation on theme: “ROLE OF ALLOGRAFT BIOPSY IN THE MANAGEMENT OF TRANSPLANTED PATIENT.)Parmjeet Randhawa,Professor, Division of Transplantation
Department of Pathology, University of Pittsburgh.
The vacuolization that results from CNI-related vasoconstriction usually begins in the proximal tubules. This is further followed by vascular injury with loss of smooth muscles, myocyte vascularization, and necrosis ending with hyalinosis which is usually focal (focal hyalinosis).
Other causes of tubular injury (osmotic, ischemic) may lead to cytoplasmic vacuolization. Also, lipiduria seen in nephrotic syndrome may show a similar picture.
https://www.sciencedirect.com/science/article/pii/S246802491730428X
Stripped interstitial fibrosis:
As CNI nephrotoxicity takes a chronic pattern the hyalinization of arterioles combined with the narrowing of the lumen with give picture of striped interstitial fibrosis (band-like). This is mainly due to reactive oxygen radicals and upregulation of tGF-beta (ransforming growth factor-beta)
Picture 2
Back to the case:
to confirm diagnosis we need to check the tough level of tacrolimus keeping in mind that the toxicity is not dose or level-dependent (at least at the time of test ) as the histologic changes which seem to be chronic (as hyalinosis ensued). we need to stain for c4d to rule out simultaneous reasons of AKI. after making sure about toxicity we need to adjust the dose if found high or just shift to m-TOR inhibitor.
CNI induced vacuolations is isometric vacuolation of the proximal straight tubules.
osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells, Osmotic nephrosis can be induced by many different compounds, such as sucrose, hydroxyethyl starch, dextrans, and contrast media.
Development of osmotic vacuolization of proximal tubular epithelial cells following treatment with sodium-glucose transport protein 2 inhibitors in type II diabetes mellitus
Peter Liptak , Bela Ivanyi. Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Clin Pract Nephrol. 2006 Jul;2(7):398-404.
Osmotic Nephrosis: Acute Kidney Injury With Accumulation of Proximal Tubular Lysosomes Due to Administration of Exogenous Solutes. American Journal of Kidney Disease. Narrative Review 2008 vol (51), p 491-503.
Shun Watanabe, Naoki Sawa, Hiroki Mizuno,Masayuki Yamanouchi,Tatsuya Suwabe, Junichi Hoshino, Keiichi Kinowaki, Kenichi Ohashi, Takeshi Fujii, Yutaka Yamaguchi, Yoshifumi Ubara.Development of osmotic vacuolization of proximal tubular epithelial cells following treatment with sodium-glucose transport protein 2 inhibitors in type II diabetes mellitus patients-3 case reports. CEN Case Rep. 2021 Nov; 10(4): 563–569.
stripped interstitial fibrosis
Prolonged use of cyclosporine or tacrolimus can cause a striking interstitial fibrosis which is said to have a “striped” pattern. The striped appearance results from areas of ischemic tubular atrophy and interstitial fibrosis alternating with relatively well-preserved or even hypertrophic renal tubules. The underlying cause may be a drug-induced thickening and hyalinization of arterioles running parallel to each other in the cortex. As the narrowing becomes significant,a linear zone of renal parenchyma situated in the water-shed zone between adjacent vessels is deprived of its nutrition and begins to undergo degenerative changes. A direct toxic effect of the drugs on the cortical medullary rays and inner medullary stripes may be also involved. The striped pattern of fibrosis is not specific for drug toxicity, and can be seen in other forms of allograft injury as well like chronic rejection, recurrent of original disease.
Dell’ Antonio G, Randhawa PS. Striped pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimus. Transplantation 1999;67:484-486.
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
Calcineurin inhibitor nephrotoxicity can be distinguished by clinical history, and also by electron microscopy, which will reveal dilated endoplasmic reticulum as the cause of vacuolization. In ischemic tubular injury, vacuoles are variable in size and the regenerating-type epithelium shows brush border flattening with blebbing.1
Other causes of vacuolization:
What is meant by stripped interstitial fibrosis?
The striped appearance results from areas of ischemic tubular atrophy and interstitial fibrosis alternating with relatively well-preserved or even hypertrophic renal tubules.2
What are the other causes of this condition?
References:
Characteristics of CNI induced a vacuolation is isometric focal tubular in proximal and distal tubules,in proximal tubules cause rough fomay tubular vacuolation.
other condition cause vacuolation administration of manitol, dextran ,sucrose and radio graphic contrast media administration .
the difference is coarse and more irregular in ischemic injury.
the molecular basis of cyclosporin and TAC nephrotoxitcity is less understood but there is evidence that it may be mediated by calcinerm pathway as well..
target of TAC nephrotoxitcity
1-tubular epithelial
2-vascular endothial cells .
3-artialor myocyte.
4-interstitial fibrosis .
myocytes vacuolation;
artriolar myocyte vacuolation usullay associted with tubular vacuolation in TAC nephrotoxicity;
can be seen with rejection with intimal artitis and also amphotorcin B
conclusion
feature of TAC toxocity inculde:
1-tulular and myocyte vacuolation
2- interstial fibrosis mainly stripped fibrosis
3-artriolar hylanosis
4-glommular capillary , efferent arttiolar thrombosis and gloomular capillary duplication.
TAC nephrotoxcity occur 17 -44% of renal transplant
Stripped fibrosis
why called stripped?
because resoluation from area of ischemic tubular atrophy and interstial fibrosis alternatively with realtively well preserved or even hypertrophy tubules.
toxic effect of TAC on corticomedullary rays and medulla inner trips.
differtional diagnosis of stripped fibrosis
1- GN
2- pyelonephritis
3-renal artery stenosis
usually irreversible but improved in KFT if co exist vasospasm
Slide A vacuolations
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
CNI induced Tubular epithelial cell vacuolization is isometric.
Other conditions associated with vacuolations include:
Renal ischemia or tubular epithelial injury caused by intravenous administration
of hyperosmotic fluids (e.g., including solutions of mannitol, inulin, glucose, sucrose, dextran, hydroxyethylstarch, urea, and radiocontrast agents) called “osmotic nephrosis”.
It can be distinguished from CNI-induced acute tubular toxicity by the varying size of the vacuoles in osmotic nephrosis, in contrast to cyclosporine-induced vacuolization, which is isometric.
Intravenous immunoglobulins can also cause vacuolization of tubular epithelial cells, with macrovacuolar appearance.
Reference:
1) Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009 Feb;4(2):481-508. doi: 10.2215/CJN.04800908. PMID: 19218475.
2) Liptak P, Ivanyi B. Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Clin Pract Nephrol. 2006 Jul;2(7):398-404; quiz following 404. doi: 10.1038/ncpneph0225. PMID: 16932468.
3) Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: Osmotic Tubular Injury. Am J Kidney Dis. 2017 Feb;69(2):e11-e12. doi: 10.1053/j.ajkd.2016.12.003. PMID: 28115065.
Slide B showed stripped interstitial fibrosis.
What is meant by stripped interstitial fibrosis?
Striped interstitial fibrosis is characterised by a band-like pattern (seen characteristically in chronic CNI-induced nephrotoxicity) with the interstitium showing prominent patchy fibrosis and corresponding tubular atrophy. It is preferentially present in the medullary rays.
What are the other causes of this condition?
Hypertensive kidney disease can also produce a similar lesion, but will show duplication of internal elastica.
Other causes of fibrosis and atrophy include:
1) Chronic AMR: concentric intimal fibrosis of arteries and transplant glomerulopathy (double contours of the glomerular capillary basement membranes), usually with positive C4d in peritubular capillaries
2) Chronic pyelonephritis or reflux nephropathy with characteristic jigsaw pattern scarring, obstruction with dilatation of tubules and Bowman’s spaces
3) Viral infection with characteristic viral cytopathic changes.
Reference:
Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. Am J Kidney Dis. 2017 May;69(5):e23-e24. doi: 10.1053/j.ajkd.2017.02.002. PMID: 28434527.
referrences
1-Starzl TE, Fung J, Jordan M, Jain A, Alessiani M, Todo S, et al. Kidney transplantation under FK506. JAMA. 1990;264:63–67. [PMC free article] [PubMed] [Google Scholar]
2-. Todo S, Fung JJ, Starzl TE, et al. Liver, kidney, and thoracic organ transplantation under FK506. Ann Surg. 1990;212:295–305. [PMC free article] [PubMed] [Google Scholar]
•NDT Plus. 2009 Apr; 2(2): 175–176.Published online 2009Feb4. doi: 10.1093/ndtplus/sfp007
hpf of renal tubule shows marked epithelial cell swelling dt numerous tiny clear cytoplasmic vacuoles caused by CNI toxicity
•“striped” pattern results from areas of ischemic alternating with relatively well-preserved or even hypertrophic renal tubules.
Results from drug-induced thickening & hyalinization of arterioles running parallel to each other in the cortex.
With progressive narrowing, a linear zone of renal parenchyma present in the water-shed zone between adjacent vessels is deprived of its nutrition & begins to undergo degenerative changes.
The striped pattern of fibrosis is not specific for drug toxicity.
It can be seen in other forms of allograft injury as well
•Dell’ Antonio G and Randhawa PS Striped pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimusTransplantation 1999;67:484-486.
•
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
Vacuolization in proximal tubule due to CNI toxicity is isometric and can be differentiated from Vacuolization due to other causes like high blood sugars, contrast media etc by Electron Microscopy. EM will show dilated endoplasmic reticulum in CNI toxicity and isometric vacuolization. In other causes vacuoles may be variable in size with regenerating epithelium showing brush border flattening ad blebbing.
What is meant by stripped interstitial fibrosis?
CNI toxicity may manifest as stripped interstitial fibrosis on Renal biopsies . The stripped pattern results from more pronounced ischemia and fibrosis in the anatomical areas alternating with well preserved areas.
What are the other causes of this condition?
Diabetes, Hypertension, viral infections, reflux nephropathy, chronic pyelonephritis
Reference
AJKD atlas of renal Pathology
Striped Interstitial fibrosis
Isometric Vacuoles in proximal tubule
Calcineurin inhibitor (CNI) nephrotoxicity may occur any time after initiation of therapy and can affect transplant or native kidneys and present as acute or chronic reductions in kidney function. Elevated serum CNI trough levels may help make the diagnosis, although CNI nephrotoxicity is not necessarily dosed dependent. CNI can cause vasoconstriction and increased serum creatinine (Scr) in the absence of morphologic findings, so CNI toxicity can be suggested as the cause of an abrupt Scr rise without morphologic changes. CNI nephrotoxicity–related acute injury is reversible with a change in immunosuppression therapy; chronic injury is not reversible.
Light microscopy: Vasoconstriction-related CNI nephrotoxicity shows no morphologic changes. Isometric vacuolization of proximal tubular epithelium and vascular injury with loss of smooth muscles, myocyte cytoplasmic vacuolization, and dropout from necrosis or apoptosis are characteristic of acute CNI nephrotoxicity. Ultimately, injured myocytes are replaced by focal nodular hyalinosis and eventual hyalinosis, which can have a distinctive adventitial localization and can extend to the media of the entire vascular wall of arterioles and arteries. CNI nephrotoxicity can also cause thrombotic microangiopathy (TMA) involving mostly arterioles and glomerular tufts. Chronic CNI toxicity shows a striped pattern of interstitial fibrosis with proportional tubular atrophy.
Immunofluorescence microscopy: IgM and C3 staining in arterioles with hyalinosis and fibrinogen staining of thrombi in small arteries, arterioles, and glomeruli involved by thrombotic microangiopathy.
Electron microscopy: Isometric vacuoles in the proximal tubular epithelium as dilated endoplasmic reticulum and large lysosomes. Hyaline accumulation within the adventitia or media of arterioles and arteries. Glomerular endothelial swelling, expansion of lamina rara interna, and mesangiolysis are present in cases with TMA.
Slide A showed CNI leading to striking interstitial fibrosis which is said to have a “striped” pattern. The striped appearance results from areas of ischemic tubular atrophy and interstitial fibrosis alternating with relatively well-preserved or even hypertrophic renal tubules.
A direct toxic effect of the drugs on the cortical medullary rays and inner medullary stripes may be also involved. The striped pattern of fibrosis is not specific to drug toxicity and can be seen in other forms of allograft injury as well. Chronic antibody-mediated rejection (CAMR), can cause concentric intimal fibrosis of arteries and transplant glomerulopathy. Other causes such as reflux, and viral infection can cause fibrosis but each has specific morphologic findings.
Slide B-D shows vacuolations, indicating Chronic CNI nephrotoxicity.
Chronic CNI nephrotoxicity (CNI-NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI-specific arteriolar hyaline deposition from non-specific arteriolar hyalinosis. Numerous tubules filled with uniformly-sized vacuoles in the cytoplasm (isometric vacuolization) can be found in the biopsy.
Arteriolar vacuolization can be found as a non-specific histopathological finding in some biopsies; also some reported cases with the use of IVIg and sirolimus.
Tacrolimus level should be monitored and the dose should be adjusted accordingly.
References:
1. Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. American Journal of Kidney Diseases. 2017 May 1;69(5):e23-4.
2. Horike K, Takeda A, Yamaguchi Y, Ogiyama Y, Yamauchi Y, Murata M, Kawaguchi T, Suzuki T, Otsuka Y, Inaguma D, Goto N, Watarai Y, Uchida K, Morozumi K. Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity? Clin Transplant. 2011 Jul;25 Suppl 23:23-7.
3. Haas M, Sonnenday CJ, Cicone JS, Rabb H, Montgomery RA.Isometric tubular epithelial vacuolization in renal allograft biopsy specimens of patients receiving low-dose intravenous immunoglobulin for a positive crossmatch. Transplantation. 2004 Aug 27;78(4):549-56.
4. Laftavi MR, Weber-Shrikant E, Kohli R, Patel S, Feng L, Said M, Dayton M, Pankewycz O. Sirolimus-induced isometric tubular vacuolization: a new sirolimus histopathologic manifestation. Transplant Proc. 2010 Sep;42(7):2547-50.
pathology slide
please see attached below
Isometric tiny numeous proximal tubular vacuolization,they are indistinguishable by light microscopy caused by CNI and osmotic toxicity.
In CNI toxicity,vacuolizations may be so focal as to affect only few tubules.
it represents dilated smooth endoplasmic reticulum in CNI toxicity . In the contrary ,vacuolization caused by other agents causing osmotic nephritis( like hypersonic sucrose solution,Mannion, high molecular weight dextran,radiocntrast material or IvIG,) represents distended lysosomes ,these diferences are distinguished by EM.
Furthermore Ethylene glycol poisoning and hypokalemia cause very large,course vacuolization..
Regarding stripped interstitial fibrosis:
It’s representing areas of interstitial fibrosis and tubular atrophy IFTA, alternating with areas of relatively preserved interstitial architecture. Its a feature of chronic CNI nephrotoxicity.
Differential Diagnosis of stripped fibrosis:
1)pre-existing donor injury.
2) Aging.
3) Tubulointerstitial rejection.
4) Infection,UTI, BKV infection,CMV.
5) Chronic Ischemia
6) Ischemia-reperfusion injury.
7) Obstructive nephropathy.
Reference:
1) AJKD Atlas of Renal pathology II,American Journal of kidney disease .www.ajkd.org.
2) A Karolin,Calcineurin inhibitor toxicity in solid organ transplantation.www.karger.com
Vacuolization of proximal tubule
Nodular haylinosis
Calcineurin inhibitor nephrotoxicity can be distinguished by clinical history, and also by electron microscopy, which will reveal dilated endoplasmic reticulum as the cause of vacuolization with the vacuoles being ismetric , involving the proximal tubular epithelium.
( although the vacuoles represent less specific feature of CNI nephrotoxicity )
other causes of vacuolations include
here the vacuoles are also isomertic
source :AJKD Atlas of Renal Pathology , sorry for not attaching a slide due to technical fault
Striped interstitial fibrosis :
The striped appearance results from areas of ischemic tubular atrophy and interstitial fibrosis involving the medullary rays ( which are more susceptible to ischemia) alternating with relatively intact tubulointerstitium . ( so like stripes of fibrosis ) , this usually occurs with chronnic CNI nephrotoxicity
Other causes of this condition
source :AJKD Atlas of Renal Pathology , sorry for not attaching a slide due to technical fault
Q1:
Vacuolization in CNI toxicity is isometric within proximal tubule epithelial cells.
file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.pngncludes: osmotic nephrosis due to hyperosmolar agents or glucose.
In EM, dilated endoplasmic reticulum reveals CNI TOXICITY,
Q2
Means abrupt session of area of fibrosis and transition to intact parenchyma.
file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image004.pngincludes: cABMR, pyelonephritis, reflux scars. Hypertension, obstruction, viral infections diabetic kidney disease, crystals or recurrence of disease or de novo injuries.
file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image006.png
Fogo, A. B., Lusco, M. A., Najafian, B., & Alpers, C. E. (2017). AJKD Atlas of Renal Pathology: Osmotic Tubular Injury. American Journal of Kidney Diseases, 69(2). https://doi.org/10.1053/j.ajkd.2016.12.003
file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image008.png
Fogo, A. B., Lusco, M. A., Najafian, B., & Alpers, C. E. (2017). AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. American Journal of Kidney Diseases, 69(5). https://doi.org/10.1053/j.ajkd.2017.02.002
CNI vacuolation:
isometric tubular vacuolation, predominantly affecting the proximal straight tubules.
The vacuoles are small, clear and distributed throughout the cytoplasm. Focal tubular calcification might also be present figure 1
The differentiation of CI-associated arteriolopathy from hypertensive or diabetic arteriolar hyalinosis is usually easy owing to the presence of focal nodular deposits that are situated inside of intact smooth muscle cells in the latter, in comparison to the deposits in CI-associated arteriolopathy, which are circular and replace necrotic smooth muscle cells. However, in advanced cases of hypertensive or diabetic arteriolopathy, or in late stages of CI-associated arteriolopathy, differentiation by light microscopy may be difficult or even impossible. Because of the rarity of CI-associated arteriolopathy in patients with autoimmune diseases and the increased frequency of unspecific arteriolar hyalinosis, the latter may be considered to be a forme fruste of the more typical lesions.
By electron microscopy, these vacuoles are dilated endoplasmic reticulum.
In osmotic nephrosis, the vacuoles are larger and are in late stage may contain an amorphous electron-dense material. It is identified as lysosomes. Figure 2
(1) CNI toxicity
(2) osmotic nephrosis
(3) strip fibrosis in CNI
1. Leal R, Tsapepas D, Crew RJ, Dube GK, Ratner L, Batal I. Pathology of Calcineurin and Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation. Kidney Int Reports [Internet]. 2018;3(2):281–90. Available from: https://www.sciencedirect.com/science/article/pii/S246802491730428X
2. Characteristics P. Osmotic Nephrosis : Acute Kidney Injury With Accumulation of Proximal. 2008;51(3):491–503.
3. Benway CJ. Defining a microRNA-mRNA targetome for calcineurin inhibitor induced nephrotoxicity Defining a microRNA-mRNA targetome for calcineurin inhibitor induced nephrotoxicity A thesis submitted by for the degree of in Sackler School of Graduate Biomedical Sciences. 2019;(May 2017).
Striped fibrosis ie fibrotic areas intermittent with normal area (3)
osmotic nephrosis
osmotic nephrosis
striped fibrosis
I could not attach all of them together
Q1:
Vacuolization in CNI toxicity is isometric within proximal tubule epithelial cells.
Differential diagnosis includes: osmotic nephrosis due to hyperosmolar agents or glucose.
In EM, dilated endoplasmic reticulum reveals CNI TOXICITY,
Q2
Means abrupt session of area of fibrosis and transition to intact parenchyma.
Differential diagnosis includes: cABMR, pyelonephritis, reflux scars. Hypertension, obstruction, viral infections diabetic kidney disease, crystals or recurrence of disease or de novo injuries.
“fig2” image reference: Fogo, A. B., Lusco, M. A., Najafian, B., & Alpers, C. E. (2017). AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy. American Journal of Kidney Diseases, 69(5). https://doi.org/10.1053/j.ajkd.2017.02.002
“fig1” image reference: Fogo, A. B., Lusco, M. A., Najafian, B., & Alpers, C. E. (2017). AJKD Atlas of Renal Pathology: Osmotic Tubular Injury. American Journal of Kidney Diseases, 69(2). https://doi.org/10.1053/j.ajkd.2016.12.003
Although there is no pathognomonic feature for CNI toxicity ,the presence of isometric vacuolization (mean equal in size)suggesting CNI toxicity .
Other condition that cause similar pathological finding are ischemic or osmotic kidney injury ( IV Ig desensitization protocol ,contrast induced nephropathy ,mannitol or sucrose .
Strip fibrosis pathological feature refer to column of fibrosis area in alternatively arrange with normal kidney tissue caused by CNI toxicity ,chronic infection ,rejection and viral infection
AJKD
Slide A vacculations of CNI toxicity
Slide B stripped fibrosis of transplant glomerulopathy
Under Light microscopy BX: showed ;
a. fine isometric vacuoles in the PCT epithelial cell( ?? Acute CNI toxicity ).
DD: osmotic nephrosis caused by administration of osmotic substance like mannitol, sucrose containing IVIG and radio contrast agents cad make ischemic tubular vacuoles.
b. stripped fibrosis pattern and tubular atrophy (??chronic CNI toxicity picture).
DD: chronic ABMR, chronic pyelonephritis, viral infections, scarring and diabetic kidney disease
C and d : nodular hyaline arteriosclerosis as in ; DM, HTN
Any more tests required to confirm your diagnosis? TAC trough level , Urine analysis, ptn/creat. ratio , DSA level , CMV PCR , BK
Management : Reduce TAC dose , FU KFT , monitor proteinuria , may add m-tors inhibitors, fu DSA levels accordingly.
Describe the significant features of the biopsy?
Light microscopic picture, stained with H and E stain :
A. fine isometric vacuoles in the PCT epithelial cell(dilated endoplasmic reticulum under EM). Feature of acute CNI toxicity
DD: osmotic nephrosis caused by administration of osmotic substance like mannitol, glucose, sucrose and radio contrast agents resulting in ischemic tubular vacuoles that are variable in size(lysosomes containing the culprit substance under EM)
B. striped fibrosis pattern and tubular atrophy, characterized by abrupt transition between linear bands of IF/TA and the intact areas of the tubule-interstitium(feature of chronic CNI toxicity)
DD: chronic ABMR, chronic pyelonephritis, viral infections, scarring and diabetic kidney disease
C and D shows nodular hyaline arteriosclerosis
DD: diabetes, hypertension, aging
Most likely diagnosis is chronic CNI toxicity
Any more tests required to confirm your diagnosis?
1- TAC trough level(But even with target trough levels, CNI toxicity cannot be excluded).check for history of drugs that can increase TAC level like macrolides
2. Urine examination and check for proteinuria
3.check serum electrolytes as markers of CNI toxicity(K, Mg, NA levels)
4. Monitor DSAs and C4D staining
5. exclude infections, BK-PCR and SV 40 staining, CMV-PCR
What is your management plan?
o Reduce TAC dose if medications that inhibit cytochrome p 450 are excluded,
keep level between 3.5-5 ng/ml with frequent monitoring of drug level
o MMF dose can be increased to a total of 3 gm/day
o Follow renal functions and proteinuria
o Adequate control of blood glucose level and blood pressure
o Switch TAC to Sirolimus if proteinuria<1gm, eGFR >40 ml/min
o Monitor DSAs with this change in immunosuppression
References:
the Biopsy shows features of mostly CNI toxicity in the form of the following:
Indeed, the following tests are required:
i may opt for switching to other IS medication e.g sirlomus in place of Tac.
Stain H&E under light microscopy.
Slide A: isometric tubular vacuolization of tubular cell.
Slide B: stripped fibrosis and tubular atrophy.
Slide C: nodular hyaline arteriosclerosis.
Slide D: nodular hyaline arteriosclerosis.
DD:
1- Chronic CNI toxicity.
2- Isometric tubular vacuolization DD:
A- osmotic nephrosis following intake of mannitol, glucose, sucrose, radio contrast agents, and IVIG.
3- Nodular hyaline arteriosclerosis DD: DM, HTN and aging.
4- Chronic C4d negative AMR.
1) Tacrolimus trough levels: CNI toxicity depends on dose and duration of exposure to them.
2) Urine R/M, urine PCR
3) Urea, creatinine and electrolytes.
4) Rule out BKV, CMV infections
5) Monitor DSAs.
What is your management plan?
Tacrolimus trough level at 3.5-5 ng/ml, increase dose of MMF.
Consider switching CNI to m-TOR inhibitor (Everolimus, or Sirolimus) if no proteinuria or less than 1g/day.
Control BP and blood sugar.
Use of Belatocept in combination with MMF and steroids, However, it should be avoided in EBV negative recipient due to the risk of PTLD.
Slide A vacuolations
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
CNI isometric cytoplasmic vacuoles are formed of enlarge endoplasmic reticulum of the proximal tubules and are usually focal in nature. CNI tubular toxicity can manifest as vacuoles or degenerative changes.
Acute CNI toxicity can manifest as ATI and vascular injury in the form of arteriolar vacuolization or endothelial swelling, or TMA.
Isometric tubular vacuolization DD: osmotic nephrosis following intake of mannitol, glucose, sucrose, radio contrast agents, and IVIG.
Slide B showed stripped interstitial fibrosis.
What is meant by stripped interstitial fibrosis?
Striped fibrosis is described as linear bands of interstitial fibrosis with atrophic entrapped tubules which alternate with preserved or hypertrophic tubules.
CNIs induce thickening and hyalinization of cortical parallel arterioles, with progressive narrowing, renal parenchyma will show degenerative changes, another possible effect can happen on the stripes at the cortico-medullary and inner medullary tissues.
What are the other causes of this condition?
CNIs prolonged use, advanced diabetic glomerulosclerosis, Hypertension, viral infections, and chronic pyelonephritis.
Dear All
Thank you for your replies. 3 questions
1. What are the other pathological conditions that can cause hyalinosis?
Diabetes, aging and hypertension.
2. How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
Hyalinosis associated with CNI toxicity affects the media/periphery of the arteriolar wall, while in the other hyalinosis causes, it is predominantly subendothelial .
3. Giving this histological picture. One or more of the following options are correct:
A. Reduce CNI dose and add MMF. Correct
B. Start mTOR if eGFR is more than 40 mls/min. Correct
C. Stop MMF and add azathioprine. False
D. Start mTOR if 24hrs urinary protein is less than 2gm/day. False
E. Stop Tacrolimus and commence cyclosporine as it is less nephrotoxic. False
Biopsy :
1 isometric vacuolations of tubules
2 stripped fibrosis
3 nodular hyaline arteriosclerosis
4 nodular hyaline arteriosclerosis and vacuolations
Most probably chronic calcineurin inhibitor toxicity.
(Negative C4d , Negative DSA , raised creat )
Confirmatory tests :
* Tacrolimus trough levels: Increased probability for high tacrolimus trough levels.
*serum electrolytes K, Na , Mg , VBG
*Urine analysis and A/C ratio
Management plan:
*optomize tac dose to trough level adjustment bet 3.5 – 5 ng/ml .
*MMF Optomization may be required to increase the dose .
*control BP, blood sugar .
Describe the significant features of the biopsy?
SLIDE A SHOWS ISOMETRIC VACULATIONS
SLIDE B SHOWS INTERSTITIAL FIBROSIS ( STRIPPED )
LAST SLIDES SHOWS FEATURES OF HYALINOSIS MAINLY ARTERIAL WHICH POINTS TO PICTURE SIMILAR TO CNI TOXICITY.
tests required to confirm your diagnosis:-
CNI TROUGH LEVEL
ELECTROLYTE ASSAY K NA MG NA
GRAFT BIOPSY
CONDITION MANAGMENT
CNI dose adjustment with targeting trough levels such as 3.5 to 5
use of azathioprine if not beneficial shift m tor inhibitor
consider plasma pharesis
A- isometric tubular vacuolization.
B- stipped interstitial fibrosis
C,D arterial hyalinosis
features of CNI toxicity
1) Tacrolimus trough levels: Increased chances for high tacrolimus trough levels, but they may be normal as the severity of the biopsy findings depends on both the dose and duration of calcenuerin inhibitors.
2) Urine routine microscopic examination and urine protein creatinine ratio spot: to look for proteinuria.
3) Serum Potassium, Serum magnesium, Serum Uric acid, ABG: CNIs are associated with hyperkaleima, hypomagnesemia, metabolic acidosis and hyperuricemia.
4) It is important to take history regarding
a) immunosuppression non-adherence/ erratic drug intake with history of fluctuating tacrolimus drug levels
b) history of any other medications like use of azoles, erythromycicn, diltiazem, IVIG, IV mannitol, IV contrast
c) History regarding blood sugar control
– CNI minimization, increment of MMF dose to 3 gm.
If this does not work, other option is to stop CNI and start mTORi if eGFR>40 and proteinuria is less than 1 gm
– Manage A/E associated with CNI toxicity (hypertension, hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, & hyperuricemia
– Calcium channel blockers such as amlodipine or nifedipine, has been shown to improve BP control & maintain glomerular filtration
– ACEi can decrease CNI induced nephrotoxicity & improved alterations in BP.
References:
Sawinski D, Trofe-Clark J, Leas B, Uhl S, Tuteja S, Kaczmarek JL, French B, Umscheid CA. Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis. Am J Transplant. 2016 Jul;16(7):2117-38.
Histopathology reveals features of chronic CNI toxicity
A:
Isometric Vacuolization of the proximal tubular epithelial cells
B:
Focal areas of tubular atrophy and interstitial fibrosis; striped fibrosis C & D: Nodular Hyaline Arteriosclerosis
Following tests and history are required:
_TAC trough levels
_History of using medications which could lead to isometric vacuolization including mannitol, IVIG and IV contrast.
_Serum potassium, magnesium, uric acid ,calcium, phosphorus as markers of CNI toxicity
_Medication history which could increase TAC level such as Azoles &, Amiodarone
_Drugs which inhibit p-glycoprotein mediated efflux of CNIs from tubular epithelial cells, which intern result in local renal exposure of CNIS- like Azithromycin, Amiodarone, Carvedilol,& Verapamil
Treatment plan:
_CNI dose minimization – with targeting trough levels such as 3.5 to 5 ng/ml
_ CNIs withdrawal is associated with more acute rejections and DSAs
_Azathioprine, if in use can be shifted to MMF
_ Control of blood pressure and management 0f dyslipidemia
References:
Sawinski D, Trofe-Clark J, Leas B, Uhl S, Tuteja S, Kaczmarek JL, French B, Umscheid CA. Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis. Am J Transplant. 2016 Jul;16(7):2117-38. .
In case of vacuolization in renal transplant we should take our care to exclude concomitant rejection since vacuolization in presence of rejection reflect tubular injury rather than CNI toxicity and in this situation we need to intensifying immunosuppressive drug rather than minimization
Describe the significant features of the biopsy?
:
isometric vacuolization
strip fibrosis
arterial hyalinosis
CNI toxicity ??
Any more tests required to confirm your diagnosis?
1-drug level (tac level).
2-CPC
3-electron microscope.
4-DSA.
5-serum electrolyte.
What is your management plan?
1-minimization CNI.
2- switch from CNI to MTOR inhibitor IF no contraindication (low GFR<40 or proteiuria more than 1g) .
– Describe the significant features of the biopsy
The image evidences vacualization which in this case are related to the use of Tacrolimus.
– Any more tests required to confirm your diagnosis ?
In view of negative C4d and DSA, we conclude that microcirculatory inflammation is related to other factors of renal toxicity. In view of the drugs used, Tacrolimus is the biggest possible cause, however it was not an increase in the concentration of the drug that caused these lesions, but its chronic use with deleterious effects.
– What is your management plan ?
Treatment consists of reducing the dose of tacrolimus and substitution with cyclosporine or sirulimus. Other alternative included plasmapheresis, fresh froze plasma Exchange and anticoagulation.
· file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png
a: Isometric Vacuoles in the proximal tubule epithelial cell.
b: Stripped fibrosis with an abrupt transition, typical for CNI toxicity.
c: Nodular hyaline atherosclerosis in afferent arteriole.
d: Hyaline arteriosclerosis in an arteriole.
· Q2:
CNI level (Tac trough level or cyclosporine C0 and C2 level), electrolyte levels, C4d staining, check for proteinuria, SV40 staining.
· Q3
Reduce CNI dosage and discontinue drugs that slow elimination of CNIs such as erythromycin and if necessary (with GFR>30ml /- and no proteinuria) can shift to mTor inhibitors.
■ Describe the significant features of the biopsy?
Renal biopsy shows the following
a )isometric and focal tubular vacuolations in proximal tubules.
b) Stripped interstitial fibrosis with tubular atrophy IFTA
c) and d) Arteriolar hyalinosis.
Acute CNI 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.
Hyalinosis may also occur with 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.
■Any more tests required to confirm your diagnosis?
1-Tacrolimus though level
2-Urine analysis,24 hour Urine protein.
3 HBA1C ,and blood glucose level .
4 – good history about medication that might affect tac level as erythromycin.
5- serum electrolytes; K, Mg, Na.
■What is your management plan?
1- minimize tacrolimus to lowest possible level keep trough level around 5-7 ng /ml with
Increase MMF to 1500/ day.
2- Control blood glucose level and blood pressure with addition of calcium channel blocker.
3- we may change to sirolimus if good GFR and no proteinuria .
CNI minimization uses reduced doses of CNIs to limit their nephrotoxicity.
CNI-free protocols do not show improvement in graft outcomes.
The ELITE-Symphony study is a randomized prospective trial that compared CNI avoidance and minimization strategies by randomizing recipients to 1 of 4 groups: low-dose SRL, low-dose TAC, low-dose CsA, or standard-dose CsA.
Renal allograft function was better and biopsy-proven AR rates were significantly lower in the low-dose TAC group than all other treatment groups.
Furthermore, allograft survival was better with low-dose TAC compared to standard-dose CsA and low-dose SRL.
CNI avoidance with low-dose SRL failed to show improvement in renal function, and the biopsy-proven AR rate and graft survival were significantly worse than low-dose TAC.
Many other trials have also shown that CNI avoidance protocols did not confer a benefit in GFR or allograft histology in patients treated with SRL.
Issa N. · Kukla A. · Ibrahim H.N.
Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence.Am J Nephrol 2013;37:602-612
1) Describe the significant features of the biopsy?
Slide a: Isometric Tubular Vacuolations
slide b: Stripped interstitial fibrosis
slide c: Nodular Hyaline Arteriosclerosis
slide d: Nodular Hyaline Arteriosclerosis
2) Any more tests required to confirm your diagnosis?
a) Full blood picture for feature of hemolytic anaemia and thrombocytopenia.
b) Blood Electrolyte for hyper K, hypo Mg.
c)serum uric acid for hyperuricaemia.
d)Urine calcium for hypercalciuria. Urine analysis for pathological cast.
e)VBG for metabolic acidosis.
f)Metabolic assessment for FK toxicity.
-Fasting blood sugar/ HBA1C for NODAT .
-Fasting lipid profile for hypercholesterolaemia.
g)Blood FK level.
h) ECG for LVH due to chronic hypertension.
i)CMV and BK virus viral level from serum.
j) ultrasound of renal system for evidence of renal stone.
k)Allograft biopsy specimen to proceed with C4d stain for AMR and SV40 stain for BKN
3)What is your management plan?
General management
1)Enquire further history include possibility of other over counter nephrotoxic medication.
2)Admit patient for hydration if clinically dehydrated.
3)Reduce FK dose by 30-50% titrate for lower FK level.
4)May switch FK to everolimus.
1) Describe the significant features of the biopsy?
Slide a: Isometric Tubular Vacuolations
slide b: Stripped interstitial fibrosis
slide c: Nodular Hyaline Arteriosclerosis
slide d: Nodular Hyaline Arteriosclerosis
2) Any more tests required to confirm your diagnosis?
a) Full blood picture for feature of hemolytic anaemia and thrombocytopenia.
b) Blood Electrolyte for hyper K, hypo Mg.
c)serum uric acid for hyperuricaemia.
d)Urine calcium for hypercalciuria. Urine analysis for pathological cast.
e)VBG for metabolic acidosis.
f)Metabolic assessment for FK toxicity.
-Fasting blood sugar/ HBA1C for NODAT .
-Fasting lipid profile for hypercholesterolaemia.
g)Blood FK level.
h) ECG for LVH due to chronic hypertension.
i)CMV and BK virus viral level from serum.
j) ultrasound of renal system for evidence of renal stone.
k)Allograft biopsy specimen to proceed with C4d stain for AMR and SV40 stain for BKN
3)What is your management plan?
General management
1)Enquire further history include possibility of other over counter nephrotoxic medication.
2)Admit patient for hydration if clinically dehydrated.
3)Reduce FK dose by 30-50% titrate for lower FK level.
4)May switch FK to everolimus.
What are the characteristics of CNI induced vacuolations and how they are different from the vacuolations caused by other conditions?
Acute calcineurin-inhibitor-induced nephrotoxicity
■ Acute afferent arteriolopathy: 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 (rare)
Lipid containing vacuolation of proximal tubular epithelial cells can be induced by various kinds of mechanisms such as ischemia, hypokalemia, hyperosmolarity and lipid accumulation.
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
Hyaline arteriolopathy on electron microscopy. Endothelial cells are swollen. Hyaline material is present subendothelially and at sites where media smooth muscle cells have dropped out previously. Hyaline material bulges into the adventitia (asterisk). ×2,500. Abbreviations: A, apoptotic myocytes; E, endothelial cells; H, hyaline material.
What is meant by stripped interstitial fibrosis?
TGF-β can promote interstitial fibrosis by decreasing the degradation and increasing the production of extracellular matrix proteins in the interstitium.
What are the other causes of this condition?
Non specific. Can be infections, drugs, ischemia, diabetes mellitus, autoimmune vasculitis.
Dell’ Antonio G and Randhawa PS Striped pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimusTransplantation 1999;67:484-486.
Q1:
a: Isometric Vacuoles in the proximal tubule epithelial cell.
b: Stripped fibrosis with an abrupt transition, typical for CNI toxicity.
c: Nodular hyaline atherosclerosis in afferent arteriole.
d: Hyaline arteriosclerosis in an arteriole.
· Q2:
CNI level (Tac trough level or cyclosporine C0 and C2 level), electrolyte levels, C4d staining, check for proteinuria, SV40 staining.
· Q3
Reduce CNI dosage and discontinue drugs that slow elimination of CNIs such as erythromycin and if necessary (with GFR>30ml /- and no proteinuria) can shift to mTor inhibitors.
slide A & B : discussed earlier
slides C & D : nodular hyalinosis extending to the media of an arteriole
other tests to confirm CNI toxicity :
Tac level
CBC with film to exclude MAHA ( due to TMA)
Blood Glucose
lipid profile
S K , S Mg , S. uric acid
Management plan :
adjust CNI dose to the minimum target level , or switching to mTOR ( if GFR > 40 ml/min , proteinuria < 1 g /24 hr )
increase MMF /MPA dose
stop or adjust drugs that decrease CNI metabolism
Renal biopsy shows
Isometric tubular vacuolation,
Focal areas of Tubular atrophy & interstitial Fibrosis(Striped Fibrosis)
Nodular Hyaline Arteriosclerosis
All these features are suggestive of Chronic CNI toxicity
2-Any more tests required to confirm your diagnosis?
Tacrolimus trough level (if within target it doesn’t exclude chronic CNI toxicity)
Alternative agents causing vacuolization should be ruled out- Mannitol, Immunoglobulins & IV contrast. Even high blood sugars,
Urine protein/ creatinine ratio-to check for proteinuria if other drugs like everolimus is to be started .
What is your management plan?
CNI minimisation rather than CNI withdrawal would be helpful-
Switching to mTor inhibitor is another option
ACE-ARB might be beneficial
Experimental role of fish oil
CNI vacuolations :
Osmotic tubular injury.
Ischemic acute tubular injury,
Tubular injury associated with lapidarian in nephrotic syndrome.
CNI nephrotoxicity can be distinguished by clinical history, and also by electron
microscopy, which will reveal dilated endoplasmic reticulum as the cause of
vacuolization. In ischemic tubular injury, vacuoles are variable in size and the
regenerating-type epithelium shows brush border flattening with blebbin.(1)
Stripped interstitial fibrosis:
which band like fibrosis, with fibrotic area abrupt separated by normal area
many causes:
hypertension, calcineurin inhibitor (CNI) toxicity, chronic pyelonephritis, reflux and/or
obstruction, viral infections, diabetic kidney disease, crystals (eg, calcium phosphate), or
recurrence of disease or de novo injuries.(2).
References:
1-AJKD Atlas of Renal Pathology: Osmotic Tubular Injury.
2-AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/Tubular Atrophy.
Vacuoles in proximal tubules.
Stripped Fibrosis.
Hyalinosis of arterioles and arteries
.
Feature of CNI toxicity.
Minimization of CNI therapy (using a lower-than-standard dose) rather than
Withdrawal (gradual elimination of the CNI) or conversion (switching from a
CNI to an alternate immunosuppressive agent) of CNI therapy.
We minimize CNI therapy by targeting lower trough levels (such as 3.5 to 5
Ng/mL for tacrolimus and 75 to 125 ng/mL for cyclosporine
a- Tubular vacuolation
b- Stripped interstitial fibrosis and tubular atrophy
c- Arteriolar hyalinosis “focal “
d- Arteriolar hyalinosis and tubular vacuolation
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.
Medical history (DM) and drug history are neded (like contrast exposure which give also vacuolation on biopsy, use of erythromycin, antiepileptic etc interact with tacrolimus CP450 enzyme metabolism).
2- serum electrolytes; K; Mg, Ca+m Na,
Tacrolimus though level
Urine examination for active urinary sediments, proteinuria.
e GFR
3- minimize tacrolimus to lowest possible level (5 – 7)
Increase MMF dose and steroid dose
If he has minimal proteinuria or no and e GFR > 40 can substitute tacrolimus by sirolimus.
Close follow up with monitoring of the renal profile and drug level
Control blood pressure with calcium blocker drugs
The Renal biopsy here shows features of chronic CNI toxicity including-
A- Isometric tubular vacuolization
It is small isometric Vacuolization in proximal tubule. These can also be seen due to other causes like high glucose levels, contrast medias, IVIG and mannitol. Vacuolization in proximal tubule due to CNI toxicity and other causes can be differentiated by Electron Microscopy. EM will show dilated endoplasmic reticulum in CNI toxicity and isometric vacuolization. In other causes vacuoles may be variable in size with regenerating epithelium showing brush border flattening ad blebbing
B- Striped interstitial fibrosis
C&D Nodular arterial hyalinosis
What further tests??
CNI trough levels – This will help in reaching the diagnosis but we have to keep in mind that even with target trough levels CNI toxicity cannot be excluded.
Magnesium levels- Low levels may suggest CNI toxicity
Other serum chemistry including Uric acid, Potassium , calcium, Blood sugar levels.
Urine protein to creatinine ratio to assess the level of proteinuria while considering starting everolimus
Management Plan
First step will be adjusting the dose of tacrolimus to keep trough levels between 5-7 ng/ml.
Switching to everolimus can be considered
Control blood pressure
Those on azathioprine can switched to MMF.
Reference
1-Peter Liptak & Bela Ivanyi. histopathology of calcineurin-inhibitor toxicity in renal allografts.Nature clinical practice nephrology. 2, pages398–404 (2006).2-Karlin A, Genitsch V, Sidler D.Calcineurin inhibitors toxicity in solid organ Transplantation. Pharmacology.2021;106:347-355
Describe the significant features of the biopsy?
In the first slide which is H &E slide, showed isometric vacuolization of the proximal tubular epithelial cells .
In the second slide in Low power H &E showed stripped fibrosis .
The third and four slide in high power we see areas of arteriolar hyalinosis.
The above findings could be described in chronic CNI toxicity.
Any more tests required to confirm your diagnosis?
1-Serum trough levels of tacrolimus
2-investigation to exclude other causes of rising serum creatinine in transplant patient
– Exclude infection
– Exclude rejection
– U/s to exclude urological causes
What is your management plan?
1-Adjust the Tacrolimus dose according to the trough level.
2-Revew his medication and hold any offending agent
References
Lusco,M.A., Fogo, A.B., et al. AKJD atlas of renal pathology : Calcineurin inhibitor nephrotoxicity. Am J Kid Dis. Volume 69(5) : E21-E22, 2017. https://doi.org/10.1053/j.ajkd.2017.02.003
Management plan
References :
Significant features of the given biopsy
Light microscopy : Isometric vacuolization of proximal tubular epithelium, and vascular injury with loss of smooth muscles, myocyte cytoplasmic vacuolization. All of these features are characteristic of CNI nephrotoxicity.Eventually, injured myocytes are replaced by focal nodular hyalinosis and gradually hyalinosis, this can have adventitial localization and extend to the media of the entire vascular wall of arterioles and arteries. Chronic CNI toxicity as expressed by Slide b represents a striped pattern interstitial fibrosis with tubular atrophy that is proportional to the fibrosis.
Electron microscopy : Isometric vacuoles in proximal tubular epithelium as dilated endoplasmic reticulum and large lysosomes. Hyaline accumulation within the adventitia or media of arterioles and arteries. Glomerular endothelial swelling, expansion of lamina rare internal, and mesangiolysis can be seen if TMA occurs.
Tests to confirm diagnosis
Ref: Transplantation Reviews, 2012
The figure above demonstrates diagnosis of allograft damage.
Changes in serum creatinine and proteinuria occur late in disease progression and cannot exactly reveal the level of kidney damage.
References
Slide A shows isometric vacuolations of the tubular cells
Slide B shows interstitial fibrosis
while slides C&D show nodular hyalinosis
Tac trough level should be revised and rechecked , full blood count , CMV PCR quantitative analysis , blood pressure assessment , full electrolytes assessment , urine analysis – C&S , and 24 hrs urinary proteins .
Management includes optimal blood pressure and blood glucose control , adjusting Tac dose according to trough levels , may be shifting to cyclosporine too or mTori if possible Using ACEI may be helpful too .
Biopsy describe:
features suggested CNI toxicity in form of isometric tubular vacuolation and stripped fibrosis
more test:
tacrolmous blood level
serum chemistry . electrolytes (hyperglycemia and hyperkalemia)and CBC
urine culture .
autoimmune profile
Doppler u/s for renal artery
TAC nephrotoxicity occur 14 to 44% of renal transplant.
the molecular basis of CNI is less understood but there is evidence that it may be mediated by calcinem pathway as well.
target of TAC causing nephrotoxcitcy
1-tubular epithelial
2-vascular endothial cells
3-artirolar endothelial cells.
4-interstium (fibrosis)
vaculolazation is in tubular epithelial which is isometric ,focal and mainly affect proxmial and distal tubules
other cause of vacuolation
administration of manitol, dextran sucrose and radiograph contrast
more coarse and more irregular in ischemic injury.
stripped fibrosis:
called stripped because resoulation from area of ischemic tubular atrophy and interstitial fibrosis alternative with realatively well preseved or even hypertrophoid tubules..toxic effect of TAC on corticu medullary innertrips
differentiation diagnosis
1-GN
2-pyelonephritis
3- renal artery stenosis
plan of managment
if confirm TAC toxocitcy decrease TAC drug level
The images of the biopsy show light microscopic sections of H and E stain showing
a) Isometric vacuolation of tubules
b) Focal area showing interstitial fibrosis and tubular atrophy (stripped fibrosis)
c) Nodular hyaline arteriosclerosis
d) Nodular hyaline arteriosclerosis
These findings, in light of clinical presentation with elevated serum creatinine, negative DSA and C4d (although no biopsy section with glomerulus shown, hence difficult to rule out C4d negative AMR), points towards chronic calcineurin inhibitor toxicity.
1) Tacrolimus trough levels: Increased chances for high tacrolimus trough levels, but they may be normal as the severity of the biopsy findings depends on both the dose and duration of calcenuerin inhibitors.
2) Urine routine microscopic examination and urine protein creatinine ratio spot: to look for proteinuria.
3) Serum Potassium, Serum magnesium, Serum Uric acid, ABG: CNIs are associated with hyperkaleima, hypomagnesemia, metabolic acidosis and hyperuricemia.
4) It is important to take history regarding
a) immunosuppression non-adherence/ erratic drug intake with history of fluctuating tacrolimus drug levels
b) history of any other medications like use of azoles, erythromycicn, diltiazem, IVIG, IV mannitol, IV contrast
c) History regarding blood sugar control
If this is indeed chronic calcineurin inhibitor toxicity,
1) Adjust trough tacrolimus levels on lower side (3.5-5 ng.ml) by decreasing the dose of tacrolimus
2) Optimize dose of MMF. If on 500 mg twice a day, increase MMF to 750 mg twice a day.
3) If no proteinuria, or less than 1 gram per day (and eGFR >40), mTOR inhibitor (Everolimus) can be used in place of CNI, although there is increased risk of rejection.
4) Close monitoring of Tacrolimus drug levels, Creatinine and proteinuria
5) Use of calcium channel blockers have been shown to improve GFR (due to vasodilatory effects).
6) Other interventions including BP control, blood sugar control.
References:
1) Farouk SS, Rein JL. The Many Faces of Calcineurin Inhibitor Toxicity-What the FK? Adv Chronic Kidney Dis. 2020 Jan;27(1):56-66. doi: 10.1053/j.ackd.2019.08.006. PMID: 32147003; PMCID: PMC7080294.
2) Karolin A, Genitsch V, Sidler D. Calcineurin Inhibitor Toxicity in Solid Organ Transplantation. Pharmacology. 2021;106(7-8):347-355. doi: 10.1159/000515933. Epub 2021 Jun 15. PMID: 34130291.
3) Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009 Feb;4(2):481-508. doi: 10.2215/CJN.04800908. PMID: 19218475.
Describe the significant features of the biopsy?
LM photos with H&E staining showing the following:
a) Fine isometric vacuolization of the proximal tubular epithelial cells.
b) Striped fibrosis pattern with clear demarcation between fibrotic area & the intact cortex
c) Nodular hyaline arteriosclerosis of an afferent arteriole
d) Nodular hyaline arteriosclerosis of a non-afferent arteriole
These features are typical of CNI toxicity
==============================================
Any more tests required to confirm your diagnosis?
1. Serum trough levels of tacrolimus
2. Check BP
3. Check serum electrolytes
4. Exclude other potential causes of isometric tubular vacuolization e.g.osmotic nephrosis caused by IV mannitol, glucose, radio contrast agents, &IVIG
5. Exclude other causes of nodular glomerulosclerosis like diabetic nephropathy, amyloidosis, & LCDD light chain deposition disease
==============================================
What is your management plan?
1. Adjust Tacrolimus dose according to trough level; keep it at lower limit of normal.
2. Manage A/E associated with CNI toxicity (hypertension, hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, & hyperuricemia
3. CCB), such as amlodipine or nifedipine, has been shown to improve BP control & maintain glomerular filtration
4. ACEi can decrease CNI induced nephrotoxicity & improved alterations in BP.
Reference
Kemper, Jonna and Kniska, Kara, “Pathophysiology and treatment of calcineurin inhibitor nephrotoxicity”(2014). Kidneycentric. Paper 2. https://digitalcommons.wustl.edu/kidneycentric_all/2
The above slide in H&E stain shows-
1.isometric vacoulization (a)
2.stripped interstitial fibrosis(b)
3.arteriolar nodular hyalinosis(c,d)
So, this whole picture depicting acute CNI toxicity in background of chronic CNI toxicity,which always tells about to think about one possibility of the whole scenario as taught in medicine ,but a graft is always precious. Hence always look for other possibility.
1.Isometric vacuolization-
A.mannitol,ivig infusion,radio contrast infusion
B.early stage of ATN
hence here to look for, recent change of cni dose, any radiological intervention,any h/o diarrhoea.
2.stripped interstitial fibrosis-
A.reflux nephropathy
B.chronic pyelonephritis
C.viral infection(bkv)
3.arteriolar nodular hyalinosis-
A.aging
B.DM
C.HTN
So I will advice-
A.tac trough level
B.FBS,lipid profile,HbA1c
C.urine re me and c/s
So,if tac level is high then i ll maintain at 3-5ng/ml,and if it is normal then I ll switch into cyclosporine as tac toxicity can occur at any level along with correction of other comorbidities like HTN.
Describe the significant features of the biopsy
A- isometric tubular vacuolization.
B- stipped interstitial fibrosis
C,D arterial hyalinosis
features of CNI toxicity
Any more tests required to confirm your diagnosis
What is your management plan?
CNI minimization, increment of MMF dose to 3 gm.
If this does not work, other option is to stop CNI and start mTORi if eGFR>40 and proteinuria is less than 1 gm.
There are other therapies but of unclear benefit in CNI toxicity such as calcium channel blockers, RAS inhibitors and fish oil.
References:
# Describe the significant features of the biopsy?
photomicrograph showing the defining features of CNIT in this study: (a) proximal tubular epithelial cell showing the fine isometric vacuoles (H and E, ×400); (b) renal biopsy showing the typical striped fibrosis pattern [note the abrupt transition between fibrotic and intact renal cortex (H and E, ×200)]; (c) an afferent arteriole showing the characteristic nodular hyaline arteriosclerosis (H and E, ×400); (d) similar nodule in a non-afferent arteriole (H and E, ×400)
# Any more tests required to confirm your diagnosis?
CNI through level
Electrolytes levels
CMV ,BK screening
DSA and c4d
Lipid profile
Blood glucose level
Key Diagnostic Features:
CNI exposure
Morphologic lesions may be absent (with functional CNI-induced vasoconstriction causing reduced kidney function)
Nodular hyalinosis, particularly adventitial hyalinosis, extending to the media of arterioles and arteries
Striped interstitial fibrosis
Thrombotic microangiopathy
Isometric tubular vacuolization (less specific)
# What is your management plan?
I will control the hypertension, hyperglycemia, hyperlipidemia, electrolytes disturbance and decrease the dose of CNI keeping the level between 5-7 ng/ml ( the patient transplanted7 years ago) and optimization of dose of MMF and steroid
https://doi.org/10.1053/j.ajkd.2017.02.003
1)This Hand E stained kidney tissue biopsy shows presence of isometric vacuolization of proximal tubular cells, striped interstitial fibrosis, arteriolar hyalinization and tubular atrophy . Hence it is suggestive of chronic CNI toxicity.
2)other test required to confirm my diagnosis are
-Blood tacrolimus trough level
-FBSL, HbA1c, Se K
– viral screening
3)–If tacrolimus trough level is high , then decrease the tacrolimus dose to maintain tac trough level to 3-5ng/ml
— if tac level is within normal range, then stop tacrolimus and start mtor inhibitors – sirolimus/everolimus.
Good but look for slides to demonstrate your answer and DD of the lesion keep trying.
Back to the case:
to confirm diagnosis we need to check the tough level of tacrolimus keeping in mind that the toxicity is not dose or level-dependent (at least at the time of test ) as the histologic changes which seem to be chronic (as hyalinosis ensued). we need to stain for c4d to rule out simultaneous reasons of AKI. after making sure about toxicity we need to adjust the dose if found high or just shift to m-TOR inhibitor.
More details
Slides
Describe the significant features of the biopsy?This is a light microscopy of a renal biopsy showed isometric tubular vacuolization of proximal tubular epithelial cell also there was astriped pattern interstitial fibrosis with proportional tubular atrophy.
These features of chronic CNI toxicity and arterial hyalinosis .CNI lead to the release of vasoconstrictors, like endothelin, causing ischemic injury .
Any more tests required to confirm your diagnosis?
CNI trough level ,monitoring FBS ,electrolytes
What is your management plan?
Change TAC to Sirolimus if GFR more than 40 and protienuria less than 1g , add MMF .
Describe the significant features of the biopsy?
A- Isometric vacuolisation and medial arteriolar hyalinosis
B- Interstitial fibrosis (stripped) and leukocyte infiltrations
C- Medial arteriolar hyalinosis
D- Tubular atrophy
Common changes seen in HPE
Calcineurin inhibitor toxicity
Acute CNI nephrotoxicity
Acute arteriopathy = renal dysfunction without histological alterations
Tubular vacualization ( isometric)
Thrombotic microangiopathy (TMA)
Chronic CNI nephro toxicity
Interstitial fibrosis and tubular atrophy ( typically stripped)
Medial arteriolar hyalinosis
Glomerular capsular fibrosis
Global Glomerulosclerosis
FSGS
Juxtagloerular apparatus hyperplasia
Tubular microcalcifications
Any more tests required to confirm your diagnosis?
Tacrolimus through level
Electrolytes – hyperkalaemia, hypomagnesia, hyperchlloremic metabolic acidosis ( distal tubular acidosis) and hyperuricaemia
BKV screening
CMV screening
USG of kidneys and doppler to look for RAS/ obstructions
Screen for hypertension and diabetes ( due to CNI)
Screen for TMA
What is your management plan?
The patient has creat of 200 and egfr of 39
I would reduce the CNI to lower dose and add on MMF because CAESAR study, ELITE-Symphony and OPTICEPT trial showed combination of MMF and low dose CNI had fewer treatment failure (AR) and higher eGFR. This studies showed CNI minimisations strategy with MMF.
I would not choose mtor as studies Elite -symphony, SPIESSER and ORION showed more AR in CNI avoidance strategy
REFERENCES
Maarten Naesens et al: Calcineurin Inhibitor Nephrotoxicity Clin J Am Soc Nephrol 4: 481–508, 2009. doi: 10.2215/CJN.04800908
Calcineurin Inhibitor-Sparing Strategies in Renal Transplantation: Where Are We? A Comprehensive Review of the Current Evidence by Brian Camilleri DOI: 10.6002/ect.2015.0283
This is a light microscopy of a renal biopsy stained with H&E stain revealing isometric tubular vacuolization OF proximal tubular epithelial cell IN (a), stripped fibrosis and tubular atrophy(b), nodular hyaline arteriosclerosis in an afferent arteriole (c) and non afferent arteriole (d)
All these features point to chronic CNI toxicity .Isometric tubular vacuolization can be due to osmotic nephrosis induced by administration of mannitol, glucose, sucrose, radio contrast agents, intravenous immunoglobulins. Nodular hyaline arteriosclerosis can be caused by diabetes, aging and hypertension.
Chronic AMR can not be ruled out as it could be c4d negative AMR.
Any more tests required to confirm your diagnosis?
1- Tacrolimus trough level
2- BP
3- RBG
What is your management plan?
careful history to rule any history of over dosing, diarrhoea, drug-drug or drug-food interaction as a cause for CNI toxicity. CNI toxicity is treated with either reduction of the tacrolimus or shift to sirolimus
What are the other pathological conditions that can cause hyalinosis?
Diabetes, aging and hypertension.
How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
· Hyalinosis associated with CNI toxicity affects the media/periphery of the arteriolar wall, while in the other hyalinosis causes it is predominantly subendothelial .
· 3. Giving this histological picture. One or more of the following options are correct:
A. Reduce CNI dose and add MMF
B. Start mTOR if eGFR is more than 40 mls/min
C. Stop MMF and add azathioprine
D. Start mTOR if 24hrs urinary protein is less than 2gm/day
E. Stop Tacrolimus and commence cyclosporine as it is less nephrotoxic
I will choose (A) and (B)
1.show isometric tubular vacuolization
2.stripped interstitial fibrosis & tubular atrophy
3. arteriolar hyalinosis.
This picture consistent with Chronic CNI toxicity
-Further tests
1.CNI drug level
2.Serial tissue section
3.Electrolite measures e.g.: potassium and magnesium
4.Fasting lipid profile
5.Fasting blood glucose
Plan of management:
. Current practice and research suggests minimization of CNIs after the initial transplant period to target lower plasma concentrations appears to be safe. However, there are no studies available to date that provide evidence supporting a reduction in CNI nephrotoxicity without an increased rejection occurrence.
Managing the adverse effects associated with CNI toxicity can be challenging. Systemic hypertension is the primary adverse effect associated with renal artery constriction and activation of RAAS. Electrolyte disturbances can also result from CNI induced nephrotubular dysfunction resulting in hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, and hyperuricemia.2
Ref:
Jonna Kemper. athophysiology and treatment of calcineurin inhibitor nephrotoxicity Pathophysiology and treatment of calcineurin inhibitor. Digital Commons@Becker Digital Commons@Becker.2014. Washington University School of Medicine Washington University School of Medicine
☆This renal biopsy from a 31-year-old male who received a kidney transplant from his brother 7 years ago, 111 mismatch shows:
▪︎ Arteriopathy, with vascular hyaline deposits
▪︎ Tubular atrophy and interstitial fibrosis ( stripped fibrosis).
This picture goes with Chronic CNI toxicity
☆To confirm diagnosis:
_________________________
1. Tacrolimus Trough level ( if high this goes with chronic CNI toxicit).
2. DSA
3. Electrolites ( hypomagnesemia can predict CNI toxicity).
4. C4d staining
5. Viral screening
☆Management plan:
______________________
No specific treatment. There is a move towards increase use of CNI free maintenance IS [1]
▪︎Stop tachrolimus
▪︎Shift to sirolimus based IS ( measure Alb/ Cr ratio first)
______
Ref:
Oxford renal transplantation
1- The kidney biopsy show tubular vacuolization ,striped interstitial fibrosis and arteriol hyalinosis which are feature of CNI toxicity
2- C4d and sv40 stain for the biopsy,Tac level ,ACR ,BP monitor
3- reduce TAC or changed to mTOR if GFR more than 40 and proteinuria less than 1g,add MMF
1-Slide a show isometric tubular vacuolization
Slide b show stripped interstitial fibrosis & tubular atrophy
Slide c and Slide d show arteriolar hyalinosis.
2-Further tests
DSA titer
C4d stain of biopsy
CNI drug level
Need biopsy section showing glomeruli
Blood Pressure monitor
Systemic hypertension is the primary adverse effect associated with renal artery constriction and activation of RAAS.
S.electrolytes
Electrolyte disturbances can also result from CNI induced nephrotubular dysfunction resulting in hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, and hyperuricemia.
Screen for BK,CMV infection
*Chronic CNI Nephrotoxicity
irreversible deterioration of renal function as a result of interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, as well as glomerulosclerosis.
Part of the mechanism of chronic interstitial nephritis is thought to be influenced by the acute effects. These include afferent arteriole vasoconstriction, local hypoxia or ischemia, free radical formation, and activation of the RAAS system, in particular angiotensin II and aldosterone
*CNIs have a narrow therapeutic index in which high plasma concentrations can result in acute nephrotoxicity (leading to chronic toxicity), and low plasma levels are associated with graft rejection.
Unfortunately even with therapeutic drug monitoring, local renal accumulation can occur. Research has been done in transplant recipients regarding avoidance, withdrawal, and minimization of CNIs to prevent these toxicities. Current practice and research suggests minimization of CNIs after the initial transplant period to target lower plasma concentrations appears to be safe.
3-Prevention of CNI Toxicity by :-
1- CCB
Treatment with a calcium channel blocker (CCB), such as amlodipine or nifedipine, has shown to improve blood pressure control and maintain glomerular filtration.2 In renal transplant patients, use of a calcium channel blocker has additionally shown to have better renal allograft function independent of its effects on blood pressure after one year of therapy.
2- ACEi
ACEi have decreased CNI induced nephrotoxicity and improved alterations in blood pressure. ARBs have shown to decrease the plasma levels of TGF-B and endothelin. However, creatinine clearance tends to lack improvement due to decrease filtration as a result of dilation of the efferent arteriole.
3- drugs that interact with CYP3A4/5 which can increase Tac level should be stopped
4-Treatment
After exclusion of chronic AMR we can do the following
1- minimize CNI therapy by targeting lower trough levels (such as 3.5 to 5 ng/mL for tacrolimus and 75 to 125 ng/mL for cyclosporine). Withdrawal of the CNI has been shown to be associated more acute rejection and the development of donor-specific antibodies (DSAs)
Minimization of CNIs, when combined with MMF, resulted in better kidney function, a lower risk of biopsy-proven acute rejection
2-Glucocorticoid withdrawal not recommended
So , long-term glucocorticoid therapy (prednisone 5 mg daily)
3- Switching CNI to SRL >6 months following transplantation is associated with a low risk of AR
If GFR >40ml/min
Grade I as opposed to II or III IF/TA
Those without significant proteinuria (<0.8g protein excretion/24 hours)
In contrast patients with poor graft function, heavy proteinuria and possibly recurrent glomerulonephritis do not benefit from (and may even deteriorate more quickly with) SRL conversion.
Reference
1- Jonna Kemper. athophysiology and treatment of calcineurin inhibitor nephrotoxicity Pathophysiology and treatment of calcineurin inhibitor. Digital Commons@Becker Digital Commons@Becker.2014. Washington University School of Medicine Washington University School of Medicine
2-Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, OSH Renal Transplantation.
Published online: Oct 2011
3-Up to date
What is the limiting factor for using an mTOR inhibitor other than <40 ml/min GFR?
Other limiting factor is proteinuria more than 1 gm.
1-Proteinuria more than 1 gm ,as mTOR inhibitors can further worsening proteinuria and edema
2- Pregnancy ( teratogenicity ) , reversible oligospermia in males with low testosterones level
3- Impaired wound healing in case of emergency or elective surgery especially surgery with use of other chemotherapy in case of cancer related surgical procedures
4- Interstitial pneumonitis usually improved with 2-3 weeks after stopping sirolimus.
references:
1-Campistol JM, Cockwell P, Diekmann F, Donati D, Guirado L, Herlenius G, Mousa D, Pratschke J, San Millán JC. Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation. Transpl Int. 2009 Jul;22(7):681-7. doi:
2- kidney transplantation handbook ,6th edition .
What is the limiting factor for using an mTOR inhibitor other than <40 ml/min GFR?
In addition to a hypersensitivity reaction to mTOR (which may occur as with any other medications), Early post-transplantation mTOR use may be associated with:
– Delayed wound healing (especially in recipients with a body mass index (BMI) >30 kg/m2).
– Increased risk of lymphocele and peripheral oedema.
– Sirolimus may delay recovery of renal function in patients with delayed allograft function.
– Everolimus may be associated with graft thrombosis [US Boxed Warning]: generally within the first 30 days after transplant; it may result in graft loss.
Later in the course of transplantation mTOR may be associated with:
– proteinuria up to nephrotic range.
– Peripheral oedema, lymphedema, ascites, and pleural and pericardial effusions. Therefore it should be used with caution in patients with poor tolerability to fluid accumulation e.g. cases with heart failure or advanced pulmonary disease.
– Non-infectious pneumonitis, interstitial lung disease (ILD), and/or non-infectious fibrosis have been observed with mTOR inhibitors.
References:
1) Sirolimus (conventional): Drug information. © 2022 UpToDate. (Accessed on 20 April 2022).
2) Everolimus: Drug information. © 2022 UpToDate. (Accessed on 20 April 2022).
Proteinuria > 1 g
Limitations to use of sirolimus:
_significant protinuria.
_ pregnancy, only allowed immunosupressives are steroids, azathioprine and CNI.
_ early post operative as it delay wound healing, or before any elective surgery especially in obese and diabetic patients with poor wound healing.
_ high immunological risk as it is weaker than CNI.
_ also uncontrolled dyslipidemia as in diabetes mellitus .
proteinuria more than 1 gm
Proteinuria more than 1 gram per day
Proteinuria more than1 gram
Proteinuria more than 1g.
Concomitant use with MMF cause bonne morrow suppression so need to minimizing MMF by 50 percent .
Concomitant use with TAC may enhance TAC toxicity .
4 graft biopsy images stained with PAS stain show:
(a) isometric tubular vacuolization
(b) stripped interstitial fibrosis & tubular atrophy
(c) & (d) arteriolar hyalinosis.
These are features of CNI nephrotoxicity ( chronic). It can occur with high trough level or even within therapeutic level. We need the following investigations:
The dose of Tac need to be reduced & stop any drugs that interact with CYP3A4/5 which can increase Tac level. The treatment options are limited to minimize CNI exposure at the risk of suboptimal immunosuppression, so conversion to belatacept may stabilized eGFR in patients with chronic CNI nephrotoxicity.
References:
1. Picture a L/M stained by H, E showing PCT with micro isometric vacuolization
2. Picture b low power L/M stained by H, E showing stripped fibrosis
3. Picture c,d L/M stained by H,E showing arterial hyalinosis
This picture is more compatible to chronic use of CNI after 7years of kidney transplantation. But other causes should be excluded
· Full history of the patient, other comorbidities (DM, HTN), medications compliance, previous trough levels, previous rejection episodes
· Examination and signs of CNI toxicity showed be reviewed
· Investigations like tac level, virology screening(cmv,EBV,bk), proteinuria
Regarding management
-tac trough level 3.5-5 ng/dl with full dose of MMF and steroids.
-shifting to Mtor is not preferred in this GFR specially if there is proteinuria more than 800mg/24h.
-balatacept is an option after diagnosis of EBV status but our center has no experience in its use.
– Significant features of the biopsy:
Isometric vacuolization of tubular epithelium
vascular injury with loss of smooth muscles,
myocyte cytoplasmic vacuolization
arteriolar hyalinosis
striped pattern interstitial fibrosis .
likely Chronic CNI nephrotoxicity
– CNI trough level
SV40 biopsy staining
BK PCR
DSA monitoring
e GFR and protein/creatinine ratio estimation
– Chronic CNI nephrotoxicity could be irreversible meanwhile if Tac trough level is high it will be decreased, if not high then it can be stopped and if e GFR and proteinuria is acceptable Tacrolimus can be substituted by m TOR .
Dear All
Thank you for your replies. 3 questions
1. What are the other pathological conditions that can cause hyalinosis?
2. How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
3. Giving this histological picture. One or more of the following options are correct:
A. Reduce CNI dose and add MMF
B. Start mTOR if eGFR is more than 40 mls/min
C. Stop MMF and add azathioprine
D. Start mTOR if 24hrs urinary protein is less than 2gm/day
E. Stop Tacrolimus and commence cyclosporine as it is less nephrotoxic
The reference of this scenario for future reading: https://www.ijpmonline.org/article.asp?issn=0377-4929;year=2010;volume=53;issue=4;spage=651;epage=657;aulast=Sharma
1-Hyalinosis occurs in hypertension and diabetes-related injury.
Hypertension related hyalinosis is subendothelial and intimal; however, nodular medial hyalinosis does occur, particularly in more severe hypertension.
Diabetic nephropathy has hyalinosis of both afferent and efferent arterioles. Transmural hyalinosis in advanced disease can make differentiation of causes
difficult.
2-In CNI toxicity there is nodular hyalinosis, particularly adventitial hyalinosis, extending to the media of arterioles and arteries
Lusco M A , eta l. Am J Kidney Dis. 2017;69(5):e21-e22
3- A and B
The patient is already on Tac-based triple therapy.
For option A, here augmenting baseline MMF is the acceptable alternative. With total WBC, absolute neutrophil, and lymphocyte counts allowing, we may increase the baseline MMF dose up to 3 gm.
1 .other pathological conditions causing Hyalinosis are commonly diabetes and hypertension.
2 .CNI toxicity cause nodular arteriolar hyalinosis , but in diabetes it may be present within the glomerular tuft under the endothelial cells or under the parietal epithelial cells (capsular drop). Hyalinosis of afferent and efferent arterioles is also common andit is not even pathognomonic.
3.A,B and D
What are the other pathological conditions that can cause hyalinosis?
The most typical medical condition associated with arteriolar hyalinosis is DM. Diabetic nephropathy is characterized by Arteriolar hyalinosis and arteriosclerosis of larger vessels, likely representing the combined effect of hyperglycemia and hypertension.
How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions?
It may be impossible to give a confirmed diagnosis based on the histological features alone in most early cases. However, a careful history and other laboratory investigations may suggest one diagnosis more than the other.
Late presentation is associated with typical pathological characteristics like; stripped fibrosis with CNI toxicity and glomerular mesangial expansion (Kimmelstiel-Wilson nodules) in diabetic nephropathy.
Giving this histological picture. One or more of the following options are correct:
My answer is A and B. This case was already on triple therapy. The point is to add strong antimetabolite to compensate for the reduction of CNI.
References:
John Vella and Daniel C Brennan. Kidney transplantation in adults: Chronic allograft nephropathy. © 2022 UpToDate. (Accessed on 19 April 2022)
(C) Arteriole with an intimal accumulation of hyaline material with significant luminal compromise (arrowhead).
(D) Renal tubules and interstitium in advancing diabetic kidney disease, with thickening and wrinkled tubular basement membranes (double arrow), atrophic tubules (thick arrow), some containing casts, and interstitial widening with fibrosis and inflammatory cells (dashed arrow). All sections were stained with period acid–Schiff stain.
Microscopic picture of the nodular accumulation of mesangial matrix, forming Kimmelstiel–Wilson nodules.
References:
Amy K Mottl, Katherine R Tuttle and George L Bakris. Diabetic kidney disease: Manifestations, evaluation, and diagnosis. © 2022 UpToDate. (Accessed on 19 April 2022).
We’ll choose slides
Any comments about intensity and shape of hyalinosis.
You can refer to the excellent review by your college Saha
Saja
Arteriolar hyalinosis occurs also with D.M and HTN.
But started sub-intimal but with CNI started mainly adventitial and extends to media.
A&B.
1- Hyalinosis occurs in hypertension and DM
2-in CNI toxicity,hyalinosis is nodular mainly in the arteriolar media while in the other causes occur as subendothelial deposits.
3- A
1-Other causes of arterial hyalinosis are diabetes,hypertension and ageing
2- The hyalinosis of CNI toxicity characterized by multilayer start form endothelial toward the entima and it is mainly happen in the arteriols the other one of DM and HTN happen in large vessels with intimal thicking
3- A&B
Q1-Arteriolar hyalinosis again is not specific pathological finding for CNIT as can be seen in other medical conditions like , uncontrolled HTN , DM , chronic TMA, APL,chronic ABMR , early post transplant finding of ah> 0( 0-3months ) indicate old age donor.
Q2-chronic CNIT arteriolar hyalinosis involve the afferent arterioles with
medial smooth muscle cells damage (no intimal lesions ) with characteristic beaded medial hyaline deposits that extended to the adventitia and appears like nodular hyaline deposits and its time dependent factor.
Q3
the correct answer A,B
A- reduce CNI and augment the dose of MMF to 1gm BID if he is already on MMF as part of triple tacrolimus based IS with CNI minimization
B- Add mTOR if GFR above 40ml/min and no significant proteinuria
For Questions C, D and E all wrong answers as azathioprine is less potent IS as MMF and might put him at risk of rejection , also presence of significant proteinuria more than 1 gm consider one of limiting factors for the initiation of m tor inhibitors as can worsening denovo proteinuria and edema and changing tacrolimus to cyclosporine add no additional benefit in-fact the chronic CNIT more with cyclosporine while tacrolimus side effects including metabolic effects like PTDM and neurotoxicity.
The best promising protocol for maintenance IS with CNI avoidance is the use of belatocept a costimulatory pathway inhibiting agent in combination with MMF and steriod but should be avoided in EBV negative recipient due to the risk of PTLD(4).
References:
1-liptak P, Ivanyi B. Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Clin Pract Nephron. 2006 Jul;2(7):398-404; quiz following 404. doi: 10.1038/ncpneph0225. PMID: 16932468.
2–inecke G, Sis B, Reeve J, et al. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant 2009; 9: 2520–2531.
3-Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation: American Journal of Transplantation 2017; 17: 1346–1357Wiley Periodicals Inc.
4- Kidney transplantation handbook ,6th edition.
Excellent and confident plan
What are the advantages of Belatacept over CNIs and what is a possible defect.
Thank you prof Dawlat
Belatocept used in many studies including RCT, all in low immunological risk groups comparing belatocept VS cyclosporine based protocols . BENEFIT ,BENEFIT-EXT trials shows that Belatocept safe with good efficacy compared to cyclosporine in low immunological risk recipients with better reno-protective benefit but with increased rate of acute rejection in the first year in Belatocept group .overall long-term graft survival and patient outcome was similar with acceptable safety profile over longterm FU( 7 years) .
denovo DSA significantly lower in belatocept group.
Belatocept should be selected in certain groups of patients like extended criteria donor with multipl comorbid and should be avoided in recipients with seronegative EBV as its associated with the risk of PTLD including CNS PTLD .
References:
1-Huber M, Kemmner S, Renders L, Heemann U. Should belatacept be the centrepiece of renal transplantation? Nephrol Dial Transplant. 2016 Dec;31(12):1995-2002. doi: 10.1093/ndt/gfw226. Epub 2016 Jun 10. PMID: 27288461.
2-Durrbach A, Pestana JM, Florman S, et al. Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study. Am J Transplant. 2016;16(11):3192-3201. doi:10.1111/ajt.13830
It was reported that switching CNI to Belatacept resulted in improvement of renal function .However, further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.
Reference:
G.Gupta et al. Am J Transplant ,Oct 2015 ,Safe conversion from Tacrolimus to Belatacept in high 8mmunologic risk kidney transplant recipients with allograft dysfunction.
Hyaline arteriolosclerosis is typically found in the kidneys of patients who have diabetes mellitus or benign arterial hypertension.
CNI toxicity has nodular hyalinosis, particularly adventitial hyalinosis, extending to the media of arterioles and arteries.
B
1-Other causes of arterial and arteriolar Hyalinosis can occurs in severe hypertension and diabetes .Hyalinosis happened in hypertension is classically subendothelial and intimal hyalinosis.Diabetic nephropathy has hyalinosis of both afferent and efferent arterioles.
2-in CNI toxicity it is a nodular medial hyalinosis.
3-Patient already on tacrolimus based therapy which is TacrolimusMMF and prednisolone.
So answer is B and D
1. What are the other pathological conditions that can cause hyalinosis?
Pre-existing donor injury, aging, diabetes mellitus, hypertension
2. How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions
CNI toxicity present with Medial arteriolar hyalinosis but other causes will have more subendothelial deposition
3. Giving this histological picture. One or more of the following options are correct:
A. Reduce CNI dose and add MMF
would reduce the CNI to lower dose and add on MMF because CAESAR study, ELITE-Symphony and OPTICEPT trial showed combination of MMF and low dose CNI had fewer treatment failure (AR) and higher eGFR. This studies showed CNI minimisations strategy with MMF
He is allredy on triple IS
Consider other options
What are the other pathological conditions that can cause hyalinosis?
Hypertension, lead to intimal fibroplasia of small arteries, and hyalinization of arterioles and Diabetes .
How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
· Hyalinosis du to CNI toxicity is nodular affect media of the arteriolar wall, while other hyalinosis causes it is predominantly subendothelial .
· 3. A and B
Aging, diabetes, and HT may cause arteriolar hyalinosis. The CNI-related picture is usually nodular affecting the media and the periphery of the arteriolar wall. The other conditions start in the subendothelium.
What are the other pathological conditions that can cause hyalinosis?
ageing, hypertension, diabetes mellitus, and focal segmental glomerulosclerosis.
Reference:
Hyaline arteriolosclerosis: New meaning for an old lesion. Kidney International. 2003;63:1162–1163.
How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
characterized by hyaline nodules that replace injured smooth muscle cells and bulge into the adventitia. With time, these growing nodules can cause significant narrowing of the arteriolar lumina. Immunostaining reveals trapping of IgM and C3 at the sites of hyaline accumulation.
Reference:
Leal R, Tsapepas D, Crew RJ, Dube GK, Ratner L, Batal I. Pathology of Calcineurin and Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation.Kidney International Reports (2018) 3, 281–290.
Giving this histological picture. One or more of the following options are correct:
For option A, MMF is already used, so we may build up the dose to 3 gm.
B. we may use mTOR if the GFR is more than 40 and the proteinuria is less than 1 gm
C. MMF is more effective than azathioprine in preventing rejection, So I will not consider this option.
D. mTOR inhibitor can be started if proteinuria is less than 1 gm.
E. I don’t find evidence supporting the conversion between CNI forms in case of CNI toxicity.
1. What are the other pathological conditions that can cause hyalinosis?
Arterial Hypertension and diabetes mellitus
2. How hyalinosis associated with CNI toxicity differs histologically from that caused by the other conditions.
Hypertension – subendothelial and intimal
DM – Transmural
3. Giving this histological picture. One or more of the following options are correct:
A. Reduce CNI dose and add MMF
B. Start mTOR if eGFR is more than 40 mls/min
1.other causes to cause arterial hyalinosis rather than CNI toxicity are diabetes and hypertension.
2. The difference in pathology is that in
a. Diabetes it affects both afferent and efferent arterioles and start in intimal then progress toward media ( transmural affection in long standing cases).
b ..Hypertension affect mainly large vessels and afferent arteriole , also start subendothelial and intimal then extends outward.
c. While in CNI induced, it starts from adventia and extends inward and has Nodular pattern , no subendothelial deposits .
3 . A and B
In case of CNI induced nephrotoxicity it is wise to decrease it’s dose with compensation with increased dose of MMF or shift to m TOR ( However, it is much weaker and can lead to higher acute rejection, also its use should follow check and exclusion of protinuria).
Hyalinosis develops in hypertension
Hypertension linked hyalinosis is subendothelial, intimal and diffuse nevertheless, nodular medial hyalinosis does occur in CNI toxicity.
3- Answer A
Causes of hyalinosis:
1)DM
2)HYPERTENSION.
3)AGING
In CNI toxicity,hyalinosis is characteristically nodular, Adventitial and extending to the media of arterioles and arteries.
Q:
A; reduce CNI and add MMF
Other causes of hyalinosis :
DM,HTN , Glomerulosclerosis(aging), ABMR.
Hyalinosis associated with CNI there’s endothelial cells involvement other causes
endothelial cells are free.
option B
1- Describe the significant features of the biopsy?
H and E stain of renal biopsy :
(a) isometric vacuoles in tubular epithelial cell
(b) striped fibrosis pattern
(c) nodular hyaline arteriosclerosis .
Mostly chronic CNI toxicity
Any more tests required to confirm your diagnosis?
1- CNI dose and trough level
2- Any recent infection or drugs
3- Investigation for viral infection as BK and CMV
What is your management plan?
1- Adjust dose of CNI according to trough level
2- Consider shifting to m TOR
3- Consider rising MMF dose
4- Treatment of any precipitating factor as BK infection
2.SV 40 staining
3.BKV RT PCR
4.Septic screen including urinanalysis & culture
2. mTORi is contraindicated because eGFR for this patient is < 40 and may be
late for conversion to mTORi and we are not told if there is any
significant proteinuria
3.One may consider cyclosporin although this is not really great idea
targeting trough of 75 -150
4.The other option is to reduce tacrolimus and aim for low trough level
around 5
5.Frequent monitoring of the trough level until its stabilizes
6.DSA monitoring as there is manipulation of the immune-suppression
7.Monitoring of allograft function by checking serum Cr
Very good