1. A 61-year-old male patient with old CKD 5 received a deceased donor kidney (76 years old), 110 mismatch, received basiliximab induction, triple immunosuppression (tacrolimus 1 mg BD, MMF 500 mg BD and prednisone 15 mg OD). His eGFR is 31 ml/min and there was no proteinuria. Tacrolimus level is 14 ng/ml. His implantation biopsy is shown below:
- What is the deferential diagnosis?
- What is your management plan?
Thanks All for your answers.
This is a typical histology of an aged kidney where there is arteriolar hyalinosis and interstitial fibrosis.
1. Since it is an aged kidney, can we give mTORi?
2. What is the difference between hyalinosis of ageing and hyalinosis of CNI toxicity?
3. Can you explain the high Tac level while this patient receives only 1mg BD?
1- yes we can give mTori
2-CNI toxicity give picture of nodular hyalinosis, but in aging, HTN, and DM it is intimal hyalinosis and spread to media of arteries
3-high Tac level in spite of low dose is related to low GFR and metabolism of Tac itself
What are the two limiting factors for shifting to Sirolimus:
Proteinuria and GFR>40
Yes prof, 1. proteinuria 2. eGFR < 40 ( > 40 is typo)
Well done Ben
Hyaline arteriolosclerosis of diabetic nephropathy and hypertension is initially intimal, progresses to involve the media, and is not typically nodular. DM affects both afferent and efferent arterioles.
A high level of TAC with such a low dose may be due to drug interaction with nonmentioned medications. I expect this patient may use concomitantly (examples may be CCB like diltiazem or verapamil usually used and needed in many cases). unexpected high tough levels of Tacrolimus may be due to many reasons; I could not get aclue in the presented case; normally, TAC will affect MMF entailing lower dose than with cyclosporin
I could not find special consideration regarding mTORIs in aged kidneys.
Better to consider GFR ( which is usually compromised in the aging kidney) to consider suitability of using MTORs.
Thank you alot; I noted that .
1- I will not recommend shifting to mTOR, the indication for mTOR is evidence of CNI toxicity or non-melanoma skin cancer, provided that the GFR is >40 ml/min, and proteinuria <800mg/day. the GFR of our patient is 31ml/min.
2-Hyalinosis of the sub-intimal layer is characteristic of ageing and chronic disease, but nodular hyalinosis of the medial and adventitial layers is caused by CNI poisoning.
3- high tac level has many causes, need to review the medications(drug-drug interaction), slower metabolism, or diarrhoea.
Excellent you realize that Sirolimus is not suitable with the given GFR.
Correct mention that the Tac level can be affected by drug interactions which are missing in this case.
Aged kidney and mTORi
Lower intensity immunosuppression such as steroid sparing regimen appear beneficial where mTORi and cyclosporine based maintenance are associated with greater potential for adverse effects.
However, mTORi have been associated with significantly reduced incidence of viral infection, which could be a direct clinical benefit in the elderly.
KDIGO guidelines regarding treatment of chronic allograft injury recommend reducing CNI and replacing it with mTORi if the eGFR is greater than 40 ml/min.
The Albany study mentions that mTORi improves mitochondrial function or biogenesis and delays cardiovascular aging in CAI.
References
Very good
Well done; glad to see you back stronger
Hyalinosis of aging vs hyalinosis of CNI toxicity
Aging kidney
Hyalinosis of CNI toxicity
References
High tac level despite low dose
References :
Excellent review of aging kidney
Excellent comparison of aging hyalinosis and chronic CNI toxicity.
But being all practicing Tx nephrologists shot is your plan for this patient.
1. Pre-transplant lesions in aged kidneys sensitize the grafts to nephrotoxic drugs, especially CNIs. So mTOR can be used as a part of CNI minimizing regimen.
CNI-free IS including ATG induction, sirolimus, MMF & steroids have been reported in dual kidneys transplantation with controversial results, showing either a clear benefit or no advantage compared with CNI-based therapy.
2. Nodular arteriolar hyalinosis is a typical, but not specific, histological finding of CNI toxicity.
No specific morphological findings are pathognomonical for the aging kidney.
Aging kidney (arterionephrosclerosis of aging) is a diagnosis of exclusion.
3. Increasing recipient age affects TAC pharmacokinetics, with higher TAC seen in older patients.
Higher trough level early post-transplant are associated with less acute rejection rates.
Reference
1. Vincent Audard, Marie Matignon, Karine Dahan, Philippe Lang and Philippe Grimbert Renal transplantation from extended criteria cadaveric donors: problems and perspectives overview
Journal compilation ھ 2007 European Society for Organ Transplantation 21 (2008) 11–17
2. L C Vázquez et al. Nodular Arteriolar Hyalinosis as Histopathologic Hallmark of Calcineurin Inhibitor Nephrotoxicity: Does It Always Have the Same Meaning? 2015 Oct;47(8):2357-60. doi: 10.1016/j.transproceed.2015.09.004.
3. Xin J. Zhou et al The aging kidney 2008 International Society of Nephrology http://www.kidney international.org
4. O’Seaghdha CM et al. Higher tacrolimus trough levels on days 2–5 post-renal transplant are associated with reduced rates of acute rejectionClin Transplant 2009: 23: 462–468 DOI: 10.1111/j.1399 0012.2009.01021.
Well done Filipe
This is ECD transplant with donor age related arteriolar hyalinosis keeping in mind the natural age-related immunosenescence mandate lower immunosuppressive medication to avoid the risk of drug toxicity and drug -drug interaction as they have altered pharmacokinetics with reduced the cytochrome P450 activity .this patient will be at risk of CNI toxicity with such high level of 14 in addition to increased cardiovascular risk and infection and malignancy, so CNI sparing or minimization should be considered and individualized like in this case. Numerous studies showed that mTOR-I have good effect on conserving kidney function (improved eGFR). Moreover ,mTOR-I was used in combination with CNI as CNI sparing regiments and their use in combination with low dose CNI showed good graft survival and low rejection rate . but however still their use limited due to safety profile and higher rate discontinuation due to many side effects including higher rate of mortality so still their use should be limited to those with low immunological risk and certain criteria like those with ECD , those at risk of malignancy , infections like BKV , CMV, skin malignancies(5.6).
i just lists few studies with references below:
2007 ELITE- SYMPHONY STUDY
low-dose tacrolimus had the lowest acute rejection rate at 1 year and had
significantly better renal function, Highest allograft survival.
In 2010 SMART STUDY
early at 10 to 24 days conversion from cyclosporine based to sirolimus. After 1 year, patients
on sirolimus had higher GFR with no change in BPAR rates. At 36 months, renal
function remained higher in the sirolimus group; however, more patients discontinued therapy in the
sirolimus group due to side effects (1).
In 2011 Spare the nephron study
Early conversion to sirolimus at 30 to 180 days after
transplant. After 2 years, renal function in the CNI withdrawal group was significantly better, with similar BPAR and graft loss rates but again side effects more in sirolimus group up to 53% (2).
In 2012 ZEUS Study
Conversion from cyclosporine to everolimus after 4.5 months post TX
A significant improvement in renal function with a mean estimated GFR difference of
5.3 mL/min/1.73 m2 in favor of everolimus was reported at 5 years, The increase in early mild acute
rejection did not affect long-term graft function or survival. (3)
BENEFIT-EXT Study using ECD and high immunological risk recipients
The belatacept groups were not inferior compared with those who received cyclosporine with overall similar graft survival at 3 years and better with sustained higher GFR in belatocept group at 7 year FU (4).
References:
1-. Weir MR, Mulgaonkar S, Chan L, et al. Mycophenolate mofetilbased immunosuppression with sirolimus in renaltransplantation: a randomized, controlled Spare-the-Nephrontrial. Kidney Int. 2011;79(8):897-907.
2. Budde K, Lehner F, Sommerer C, et al. Conversion fromcyclosporine to everolimus at 4.5 months posttransplant: 3-yearresults from the randomized ZEUS study. Am J Transplant.2012;12(6):1528-1540.
3. Budde K, Lehner F, Sommerer C, et al. Five-Year Outcomes inKidney Transplant Patients Converted from Cyclosporine to Everolimus: The Randomized ZEUS Study. Am J Transplant.2015;15(1):119-128.
4-Durrbach a., Pestana JM, Pearson T, et al. A phase III study ofbelatacept versus cyclosporine in kidney transplants fromextended criteria donors (BENEFIT-EXT Study). Am J Transplant.2010;10(3):547-557
5-Calcineurin Inhibitor-Sparing Strategies in RenalTransplantation: Where Are We? A Comprehensive Review of the Current EvidenceBrian Camilleri,1,2 Julie M. Bridson,2 Ahmed Halawa2,3: Experimental and Clinical Transplantation (2016) 5: 471-483.
6- m-TOR Inhibitors in Kidney Transplantation: A Comprehensive Review Mekki M1,2, Bridson JM2, Sharma A2,3 and Halawa A2,4* J Kidney 2017, 3:3 DOI: 10.4172/2472-1220.1000146
2. What is the difference between hyalinosis of ageing and hyalinosis of CNI toxicity?
CNI toxicity (tacrolimus, cyclosporine) include Acute toxicity which is characterized histologically by necrosis and early hyalinosis of specific smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy. While chronic CNI toxicity includes the obliterative arteriolopathy/hyalinization of the afferent arteriole, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia,focal interstitial fibrosis associated with macrophage influx, and tubular (striped fibrosis) .The severity of biopsy findings correlates with dose and duration of CNI use.
3. Can you explain the high Tac level while this patient receives only 1mg BD?
1-CYP3A5*1 polymorphism (expressors of CYP3A5; 236) had a higher risk of developing chronic CNI nephrotoxicity compared with non expressors (CYP3A5*3/*3) nephrotoxicity due to higher peak drug exposures and increased circulating CNI metabolites.
2- Drug -drug interaction like antifungal(azoles ), antiviral medication including tenovivor the use of the non- dihydropyridines CCBs, diltiazem and verapamil, can be used as CNI sparing agents to lower the total CNI dose and therefore, the cost of therapy. Diltiazem also lower the CNI induced vasoconstriction although there is no definitive evidence that diltiazem prevents chronic CNI nephrotoxicity.
Well done Saja, excellent answer as always
References:
1) Ventura-Aguiar P, Campistol JM, Diekmann F. Safety of mTOR inhibitors in adult solid organ transplantation. Expert Opin Drug Saf. 2016;15(3):303-19. doi: 10.1517/14740338.2016.1132698. Epub 2016 Jan 28. PMID: 26667069.
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) Kim IW, Moon YJ, Ji E, Kim KI, Han N, Kim SJ, Shin WG, Ha J, Yoon JH, Lee HS, Oh JM. Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients. Eur J Clin Pharmacol. 2012 May;68(5):657-69. doi: 10.1007/s00228-011-1182-5. Epub 2011 Dec 20. PMID: 22183771.
Well done Amit
1)we can consider the use of mTOR for this patient as the drug has antiproliferative and antiangiogenics effect with no nephrotoxicity so can improve patient and graft survival rate but we have to balance its use if patient has proteinuria or high body mass index .
2)hyalinosis due to aging is thickening of artioles by deposit of homogenous pink hyaline material as apart of ageing process
CNI hyalinosis different theaory
angiotensin 2 cause vasculopathy (hyalanosis)
some of studies in rates revealed TGF beta in juxtaglommular apparatus (immmuno response);most probably the cause.
3)causes of high TAC in this patient need to consider all factors below:
serum albumin,Hb,heamtocrit
concomenent medication use
genotype that influence the pharmokineticks and clinical response
presence of diarrhoea because many cases report of high TAC level associated with diarrhoea
PMID: 20214406 © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Similar articles
The aged kidney is more immunogenic than the young one in contrast to the aged recepient, with a higher risk of acute rejection, it might be explauned by escalated level of inflammation and edema induced by Ischemia reperfusion injury in aged kidney maintaining a stronger level of immune response. Therefore mTori is not advisable as in addition to what we mentioned, its primarily associated with elevated rate of acute rejection.
Regarding arterial hyalinosis, in CNi induced, its characteristically nodular and extending to the medial layer of the arteriols.
High Tac trough level could be explained by age of the recepient, genetic variability in cytochrome p450 CYP enzymes and or p glycoprotein expression, in addition to liver dysfunction.drug – dryg interaction is another pissibility, but we dont know the full list of medications used.
References:
1-Johan Noble et al, Transplantation of Marginal organs:Immunological aspects and therapeutic perspectives in Kidney transplantation. Frontiers in Immunology:31January 2020.
2-Mark A et al, AJKD Atlas of renal Pathology:Calcineurin Inhibitor Nephrotoxicity. AJKD. 2017, 69(5):e21-e22.
3-Arin S. Jantz et al. Treatment of Acute Tacrolimus Toxicity with Phenytoin in Dolid Organ Transplant Recepient. Hindawi, Case report in Transplantation vol. 2013.
1. Since it is an aged kidney, can we give mTOR?
Before starting mTOR we should consider 3 important points
-eGFR: it should be above 40ml/min
-proteinuria not more than 800-1000mg/24h
-there is no hyperlipidemia
so its better not be used at this low eGFR
2. What is the difference between hyalinosis of aging and hyalinosis of CNI toxicity?
Hyalinosis of aging is intimal but hyalinosis of CNI is mural and adventitial
3. Can you explain the high Tac level while this patient receives only 1mg BD?
o We need to revise the trend of his tac level (single reading
or all the previous readings are on the high side)
o we need to make sure that the patient is taking his medications
in the right way and tac level was done correctly.
o We need to revise his medications for possible drug X drug
interactions
o We need to revise his regular dietary and food intake in
relation to medications
o We need to revise any history of diarrhea
o this is maybe related to his cytochrome p450 activity (slow
metabolizer) and in this case, our center experience is to try to use
extended-release form very small dose of 0.5mg once daily if the level is high, we
used to shift to cyclosporin
Yes we can give if eGFR is more than 40 ml/min
-There is nodular hyalinosis in CNI toxicity but in aged patients it is intimal hyalinosis.
-High Tac level in spite of low dose is likely due to metabolic factors
1Since it is an aged kidney, can we give mTORi?
eGFR of the patient is below 40 ml /min so its better to avoid mTOR.
2 What is the difference between hyalinosis of ageing and hyalinosis of CNI toxicity?
The defining features of CNIT included at least one of the following: isometric vacuolization of proximal tubular epithelial cells, arteriolar hyalinosis with medial/peripheral nodule formation in at least one arteriole and presence of tubular atrophy and/or interstitial fibrosis (TA/IF) in a characteristic “striped” or “band” like pattern.
Hyalinosis of the sub-intimal layer is characteristic of ageing and chronic disease.
3 Can you explain the high Tac level while this patient receives only 1mg BD?
-aging is associated with an increase in relative fat content of the body and a decrease in muscle mass , resulting in a larger volume of distribution of lipophilic drugs such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORis) .
-Protein production declines with aging and protein binding is decreased by up to 15 to 25% in older compared to younger adults
, there is a decrease in albumin, which binds acidic drugs, and an increase in alpha-1-acid glycoprotein (AGP), which binds basic drugs. Tacrolimus (99%), sirolimus (91%), and mycophenolic acid (MPA) (up to 97%) are highly albumin-bound compounds,Hypoalbuminemia may lead to higher pharmacologic exposure to immunosuppressive medications.
-Drug clearance via the hepatic cytochrome P450 (CYP450) enzyme decreases with age, resulting in higher plasma levels of CNIs, mTORis, and corticosteroids.
Wisit Cheungpasitporn, Krista L.David A.Immunosuppression Considerations for Older Kidney Transplant Recipients.Current Transplantation Reports volume 8, pages100–110 (2021).
Alok Sharma1, Sumeet Jain2, Ruchika Gupta.Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies.Year : 2010 | Volume : 53 | Issue : 4 | Page : 651-657
Agree with mTor
modular hyalonosis can be occurred with toxicity of CNI on other hand in DM and HTN the hyalonosis in arteries media
Dear All
Can you explain the histological finding in the index case?
What do you think about introducing mTORi?
mTori is associated with higher risk of acute rejections, and high incid3nve of AMR. I think CNi is still indicated, but to avoid toxicity.
Arterial hyalinosis due to ageing with interstitial fibrosis.
It is difficult to use mTORi in such a case as the GFR is below 40.
arteriolar hyalinosis, and tubular atrophy are mostly age related
the difference between age-related hyalinosis and CNI toxicity, CNI chronic toxicity is mostly nodualr hyalinosis while age related hyalinosis is diffuse and subintimal.
mTORi could be used with eGFR> 40 ml/min
high tac level could be due to drug interactions or viral infection.
references
1- Arteriolar Lesions in Renal Transplant Biopsies: Prevalence, Progression, and Clinical Significance. The American Journal of Pathology (2012):180 (5);1852-1862
1) What is the deferential diagnosis?
Age related arteriolar hyalinosis and fibrosis
Chronic hypertension
No evidence of active allograft rejection.
2)What is your management plan?
Hydration
check FK level.
avoid nephrotoxic medication
ensure good BP and blood sugar control.
This aged kidney with arteriolar hyalinosis it may be due to old changes or CNI toxicity making in our minds this high level of prograf
In this situation you need to correct all causes of CNI toxicity like diarrhoea and drug drug interaction and if it still the level is high with this such low dose we can try long acting Tac (advagraf) because this patient may had slow metabolism due to genetic defect in CYP3A5 enzyme .
mTOR it not an option in this situation due to low GFR
– Aged kidney with picture of arterial hyalinosis and interstitial fibrosis
– Donor related disease; DM, HTN, TMA
– ATN
– UTI
– CNI toxicity but remote possibility if this zero-time biopsy
– Close monitoring of renal function and proteinuria level
– Monitor DSA
– Good hydration
– Avoid any nephrotoxic medications
– Monitor drug level
Biopsy findings are hyalinosis of the blood vessels and peri-tubular capillaritis,and lymphocytic infiltrate in the interstitium which may go with the following differential diagnosis :
Plan of management:
H&E stain, biopsy at the time of tranplanation.
Glomeruli: non
Tubules:non
Blood vessels-à Hyalinosis
Interstitium: Fibrosis
DD: aged kidney donation.
CNI can induce the same changes however with Zero hour biopsy, it is not expected that CNI toxicity is a DD.
High Tacrolimus level in zero hour Tx on a small dose of tacrolimus raises a question about the original native kidney disease of the recipient and was he on immunosuppressive medications before RTx, another question is this a first transplant or second transplant, finally drug interactions that might reduce metabolism of CNI?
Donor medical background.
Recipient medical background and drug history for interactions with Tacrolimus
BP conrol
Reduce dose of CNI or stop it, monitor level
m.TORi can be used later if GFR improves >40 ml/min/m2 and no proteinuria
DSA
Thanks All for your answers.
This is a typical histology of an aged kidney where there is arteriolar hyalinosis and interstitial fibrosis.
1. Since it is an aged kidney, can we give mTORi?
m.TORi can be given for aged kidney if no proteinuria and GFR> 40 ml/min/m2.
In this case GFR is 31, no proteinuria. Giving m.TORi is not advisable .
2. What is the difference between hyalinosis of ageing and hyalinosis of CNI toxicity?
CNI hyalinosis: nodular affecting afferent arterioles(medial and adventitial affection)
Ageing hyalinosis: intimal and medial of interlobular arteries affection
3. Can you explain the high Tac level while this patient receives only 1mg BD?
Slow metabolism
1. Being an old age recipient who received a graft from a deceased donor, in addition to the provided biopsy which reveals marked arteriolar hyalinosis and interstitial fibrosis, so the differential diagnosis will be:
· Most probable is aging kidney (age of donor, 71 years); characterized by marked arteriolar hyalinosis starting subintimal and affecting both afferent and efferent arterioles+ interstitial fibrosis.
· Chronic disease as diabetes and hypertension, affecting both afferent and efferent.
· CNI induced nephrotoxicity (arteriolar hyalinosis must be nodular and starting in the media, with bulge into adventitia), and stiped interstitial fibrosis.
2. Management plan for this patient:
· Although KDIGO recommends to shift from CNI to m TORi (sirolimus) in case of aging kidney to minimize further chronic changes of allograft and it has advantage of minimization or infections and malignancy in such old recipient, it is not suitable here as patient has decreased GFR < 40 ml/min/1.72 m2.
· So, the suitable option is to minimize dose of CNI to achieve target trough level.
3. As regard mTOR: as mentioned above.
4. Explanation of high tac trough level despite low dose may be”
· Genetic element; according to the cyt P single nucleotide polymorphism, being a slow metabolizer who can achieve trough level with minimal doses.
· Drug-drug interaction; use of enzyme inhibitors as ketoconazole, erythromycin and verapamil (which can inhibit metabolism of CNI), competitive inhibition of Cyt P.
· Enterocolitis : with loss of efflux protein (P-gp) that get rid of CNI, so their loss leads to higher concentration of CNI in the blood.
Having this Bx at implantation time with the findings of arteriolar hyalinosis and tubular atrophy makes aging of the donor the most probable explanation , although these changes might be related to longstanding DM &/or HT , however the donor past Medical history is not declared here.
we should aim for a lower TAC trough level by looking for and correcting the possible cause of high level , decreasing the daily dose with close monitoring , along with DSA monitoring
control of blood pressure and glucose to reduce further allograft injury
arrange for another biopsy should any further decline in eGFR or proteinuria develops
We have a 61 year old CKD V patient who has received a Marginal criteria donor age 76 years. Although the donor did not have any history of diabetes or hypertension or previous stroke, the implantation biopsy of the kidney at the time of transplantation is shown…
The differential diagnosis of the biopsy is Age related arteriolar hyalinosis, diabetes mellitus or hypertension of the donor….The biopsy is typical of the aged kidney….Chronic CNI toxicity can explain the above picture, but this was taken at the time of implantation, so it is unlikely due to CNI toxicity…
This patient has received Basiliximab induction, and is on triple immunosuppression…his eGFR is 31ml/min with no proteinuria… Patient has a very high tacrolimus level…the recommended level of tacrolimus is 5-9 ng/ml when induction agents are used….
I would reduce the dose of tacrolimus to maintain lower level of 5 to 9 ng/ml given the risk of exaggerated response of Chronic CNI toxicity….I would offer tight glycemic and blood pressure control…There is no proteinuria now…however eGFR is less than 40ml/min…I would serially monitor the renal function test and if eGF is more than 40 ml/min with proteinuria < 800mg/day, i would switch over to mTOR inhibitors…Worsening of the graft function also requires a repeat renal biopsy to rule out rejection
Answer to prof questions:
Renal biopsy of 76 years old donor showing arteriolar hyalinosis and interstitial fibrosis.
These lesios mostly related to age of the donor and his medical condtion as DM or HTH
Other lesions related to aging includ :
global glomerulosclerosis, arteriosclerosis, arteriolar hyalinization, interstitial fibrosis and tubular atrophy.
The additional background injury may also be caused by long-lasting hypertension and/or diabetes, as well as several environmental and iatrogenic factors, which are relatively common in the elderly population.
deferential diagnosis
-CNI toxicity but the hyalinosis in CNI toxicity is nodular with stripped fibrosis
-long standing hypertension and DM
What is your management plan?
-Proper control of any medical condition as HTN and DM
-decrease the dose of tacrolimus as the trough level is high
-review other drug- drug interaction that might increase tac trough level despite low dose.
-24h protein for proteinuria.
Kidney disease in the elderly: biopsy based data from 14 renal centers in Poland.Agnieszka Perkowska-Ptasinska, Dominika Deborska-Materkowska,BMC Nephrology volume 17, Article number: 194 (2016)
76 years old donor, implantation biopsy showing arterial hyalinosis and interstitial fibrosis mostly it is due to renal ageing
or other conditions in the donor as HTN or DM
chronic CNI nephrotoxicity may lead to hyalinosis but not in this patient as it is a time dependent process
CNI dose should be reduced as the donor age makes it an extended criteria donor which are more susceptible to CNI induced nephrotoxicity
When GFR improve to >40ml/min, mTORi could be considered as they improve the outcome in ECD with preservation of renal function and decrease adverse events of CNI as cardiovascular morbidity, mortality and malignancy in old aged recipients.
Control of blood pressure and blood glucose
Einecke G, Reeve J, Halloran PF. Hyalinosis lesions in renal transplant biopsies: time‐dependent complexity of interpretation. American Journal of Transplantation. 2017 May;17(5):1346-57.
Filiopoulos V, Boletis JN. Renal transplantation with expanded criteria donors: Which is the optimal immunosuppression?. World journal of transplantation. 2016 Mar 24;6(1):103.
What is your differential diagnosis??
In this case biopsy was taken at the time of transplant and there is deceased donor who is 76 year old. The biopsy shows arterial hyalinosis and interstitial fibrosis. Likely these histological findings are due to aging. Causes of these Histological findings can be due to CNI toxicity, aging and medical conditions like diabetes and hypertension.
In this case biopsy was taken at the time of transplant so CNI toxicity is ruled out
What is your management plan?
I will make sure that medical conditions like diabetes, dyslipidemia and hypertension are optimised and well controlled. It will be very important to avoid any nephrotoxic medications.
Tacrolimus levels are high although the dose is small and I will make sure that level are optimised. I will make sure that that patient is not taking any medication which is affecting metabolism of tacrolimus (effect on cytochrome P450) and rule out liver dysfunction.
There is no proteinuria but eGFR is low so shift to Sirolimus is not an option at this stage.
Mark A Lusco et al. AJKD atlas of renal pathology. CNI toxicity. Atlas of renal pathology.Vol 65 issue E 21-22
In this case, putting in data together points to an ageing renal allograft (76 age, GFR 31, biopsy showing arteriolar hyalinosis, interstitial fibrosis and tubular atrophy are prevalent too)
Management plan would be directed to adjusting medications according to geriatric metabolism (tacrolimus level can be tailored to his case) along with other post-operative follow up especially careful prophylaxis against infections and anticoagulation according to his laboratory investigations and imaging.
No change in his immunosuppressive regimen ,careful monitoring to drug level, avoiding any drug interaction , healthy lifestyle , healthy meals , monitoring of co morbidities if exist as HTN or DM .
Frequent visits weekly to his transplant center in the first early period about 3 to 6 months are mandatory.
Arterial hyalinosis and tubular atrophy after consideration of donor age and time of transplantation it more compatible with aged kidney but its nonspecific finding maybe also caused by hypertension, diabetes and chronic CNI toxicity but if its related to CNI it will be more mural and adventitial and it will be associated with other patchy finding which usually seen with chronic CNI toxicity
o better control of precipitating factors like hypertension and diabetes
o targeting lower levels of CNI: patient already on 1mg bid and his tac level is 14
o We need to revise the trend of his tac level (single reading or all the previous reading are on the high side)
o we need to make sure that patient is taking his medications in right way and tac level was done correctly.
o We need to revise his medications for possible drug X drug interactions
o We need to revise his regular dietary and food intake in relation to medications
o We need to revise any history of diarrhea
o this is maybe related to his cytochrome p450 activity (slow metabolizer) and in this case our center experience is to try to use extended-release form very small dose 0.5mg once daily if the level is high, we used to shift to cyclosporin
all causes of arteriolar hyalinosis should be consider
1)ageing process (elder donor),
2)hypertension
3)DM
4)chronic glommular nephritis.
CNI toxicity in the bottom of the list as this too early to have this condition from CNI exposure as need time up to 500 days to start to have effect
The implantation biopsy (taken at the time of transplant) shows arterial hyalinosis and interstitial fibrosis. For all practical purposes this is native kidney biopsy of the 76-year-old deceased donor signifying the donor characteristics.
Causes of arterial hyalinosis in this scenario include changes due to ageing, diabetes mellitus and hypertension (details of the donor regarding history of diabetes and hypertension, the serum creatinine has not been provided).(1) Interstitial fibrosis could also be age related or due to chronic insult to the kidney in form of high blood pressure.
This cannot be due to acute CNI toxicity because the biopsy has been taken at the time of implantation and there is no exposure of CNI to the kidney.
Details regarding the donor and the intraoperative insults (ischemia time, hypotension during surgery) need to be reassessed.
This patient has a high tacrolimus drug level; hence the dose of tacrolimus needs to be reduced.
Blood pressure and blood sugars should be monitored and controlled.
The low eGFR should be closely watched, if no improvement a transplant kidney biopsy should be done, DSA levels should be checked.
Close monitoring post-transplant. If the GFR improves later and is consistently >40 ml/min and the proteinuria is less than 800 mg/day, switching to mTORi can be considered. At present mTORi use is not advisable in view of low GFR.
References:
1) 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.
This case differential diagnosis is Calcinurine inhibitors toxicity
old donor
chronic glomerulopathy
DM
HTN
management:
history of co morbidity like DM, HTN, hyperlipidemia
monitoring of tacrolimus level by decrease dose
monitoring of DSA level
intravenous ATG therapy
it’s can use of mTOR in case of decrease GFR and no proteinuria
Dear Sahar, obviously, you have not read your colleagues’ replies. We can not give mTORi while the eGFR is below 40 mls/mins
See the replies above.
# This is a typical histology of an aged kidney where there is arteriolar hyalinosis and interstitial fibrosis.
#Arteriolar hyalinosis, or hyaline arteriolosclerosis, is a vascular lesion often found in the kidney , It consists of accumulated hyaline material, which is thought to be the result of subendothelial leakage of plasma proteinsand of subsequently increased extracellular matrix production by smooth muscle cells (SMCs) In the kidney, the afferent arterioles are the most commonly affected vessels, likely because of their role of major resistance arterioles, placing great local stress on the endothelium. It is thought that hyalinosis of the afferent arterioles leads to loss of autoregulation, which, in turn, leads to glomerular damage and the decline of renal function.
# What is the deferential diagnosis?
1) Aging process
2) Hypertension
3) CNI toxicity
4) Diabetes Mellitus
# What is your management plan?
1) Control of BP
2) Control of DM
3) Modification of the CNI dose with close monitoring for the drug level.
4) Follow up graft function
5) Follow up dyslipidemia and proteinuria
* R. Moritz, M.R. Oldt
Arteriolar sclerosis in hypertensive and non-hypertensive individuals Am J Pathol, 13 (1937), pp. 679-728.7
* A.C. Matos, N.O. Camara, L.R. REQUIaO-Moura, E.J. Tonato, T.C. Filiponi, M. Souza-DURaO Jr., D.M. Malheiros, M. Fregonesi, M. Borrelli, A. Pacheco-Silva
Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant Nephrology (Carlton), 21 (2016), pp. 923-929
Well done Elaf
this changes could be due advance age, HTN , DM ,CNI toxicity would not be relavant because the boipsy was taken at implantation time.
thia patient need rebiopsy and DSA level.
look for recurrence of the primary disease
reduce tacrolimus dose or change it.
The cause of high TAC level despite low dose could be due abnormal metabolism or drug interaction.
I think mTOR can be used.
Short and comprehensive .
But Sirolimus with GFR 31!
Here we have marked arterial hyalinosis. I could not get information about the timing, but whatever hyalinosis is seen in CNI, toxicity may occur at any time and is not dose-dependent. DM and HT also lead to arterial hyalinosis (we do not have info about the donor; as it is deceased, maybe had HT, not DM, but anyhow, eGFR was probably acceptable.
Hypertension related hyalinosis is classically subendothelial and intimal; in severe HT may be nodular medial.
In diabetic nephropathy, hyalinosis occurs in both afferent and efferent arterioles. Transmural hyalinosis in advanced disease can make distinguishing different etiologies difficult.
Also, we have fibrous may be as mentioned related to age
İntraoperative biopsy may be helpful in extended donor donation, especially if deceased
This a zero hour biopsy (intraoperaoperative)
What is the effect of acute (very short time) CNI exposure and chronic CNI exposure toxicity.
-The biopsy showed arterial hyalinosis and interstitial fibrosis.
What is the differential diagnosis?
Causes of arterial hyalinosis:
1. Older donor.
2. chronic glomerular diseases.
3.CNIs Toxicity.
4. Diabetes Mellitus.
5. Hypertension.
-This is ECD Kidney. The donor characteristics that define an ECD kidney include age > or = 60 years, or age 50-59 years plus two of the following: cerebrovascular accident as the cause of death, preexisting hypertension, or terminal serum creatinine greater than 1.5 mg/dl.
What is your management plan?
-I need a more detailed history of the donor and recipient.
-TAC level ? is high with this small dose of TAC ( Several factors affect the pharmacokinetics of tacrolimus, including the age or gender of the patient, liver impairment, and genetic variances in cytochrome P450 (CYP) enzymes and/or P-glycoprotein expression). reduce TAC dose.
-Close follow-up for TAC level.
-Control hypertension and Diabetes mellitus.
-Shifting the patient to mTOR: If no proteinuria and eGFR ˃40 mL/min/1.73 m2
References:
-G Einecke , J Reeve , P F Halloran . Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation. Am J Transplant
. 2017 May;17(5):1346-1357. doi: 10.1111/ajt.14136. Epub 2017 Jan 3.
– C. E. Staatz and S. E. Tett, “Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation,” Clinical Pharmacokinetics, vol. 43, no. 10, pp. 623–653, 2004.
-U. Christians, W. Jacobsen, L. Z. Benet, and A. Lampen, “Mechanisms of clinically relevant drug interactions associated with tacrolimus,” Clinical Pharmacokinetics, vol. 41, no. 11, pp. 813–851, 2002.
Very good clear plan.
Differential diagnosis
Renal arterial hyalinosis is seen in the histological image above. The differential diagnosis for this is below :
Management plan
References
Good but remember GFR is 31
What is your differential diagnosis?
The patient has been given an older kidney with 110 mismatch. He has been given basiliximab induction and triple IS as maintenance. His Tacrolimus level is slightly higher 14ng/ml
He biopsy showed intimal arteriolar hyalinosis and nodular hyalinosis with interstitial fibrosis. No evidences of glomerulitis and tubulitis.
Differential diagnosis of arteriolar hyalinosis
1- CNI Toxicity
2- Advanced aged donor
3- Hypertensive nephrosclerosis
4- Diabetes Mellitus
5- Less frequently in those underwent simultaneous kidney – pancreas transplant
What is your management plan?
The patient might be slow metaboliser which needed to reduce further the dose of Tac to maintain level at 8-10
screen for hypertension and diabetes for the patient
I would screen for data from the donor- history of hypertension , diabetes to aid in my management
Screen for CMV,BKV viruses
Very good
Remember (aging kidney)
☆What is the deferential diagnosis?
_____________________________________
This biopsy shows thickening of the walls of arterioles by the deposits that appear as homogeneous pink hyaline material this is most likely arterial hyalinosis [1] , there is also evidence of interstitial fibrosis, no glomeruliis present in this biopsy section
▪︎Differential diagnosis arteriolar hyalinosis [1]:
1- Advance Donor Age
2- Diabetes mellitus
3- Hypertension
4- CNI nephrotoxicity
☆What is your management plan?
_____________________________________
▪︎ To search for the cause of hayline arteriosclerosis in this case an enough data is required to see if the donor was:
a. expanded criteria donor ( ECD)* or not.
b. diabetic
c. hypertensive
▪︎Identify the cause of donor death.
▪︎ Control diabetes if present
▪︎ Control of hypertension if present
▪︎Follow the renal function and DSA level
▪︎Keeps Tacrolimus level at a lower range of normal.
_______
*Note:
ECD is defined as either aged 60 years or older at time of death or as aged 50–59 years with two of the following three criteria (a) history of hypertension, (b) serum creatinine >1.5 mg/dl, or (c) death by cardiovascular accident [2].
______________________
Ref:
[1]https://en.m.wikipedia.org/wiki/Arteriolosclerosis
[1] Fabian Echterdiek, Vedat Schwenger, et al ” Kidneys From Elderly Deceased Donors—Is 70 the New 60?” ,https://dx.doi.org/10.3389/fimmu.2019.02701
Very good
the above biopsy showed interstitial fibrosis, tubular atrophy, arterial hyalinosis
can be seen in different situations:
1- CNI toxicity
2- chronic rejection
3-chronic infection as pyelonephritis
4-recurrent disease
5-DM, HTN
6-old age kidney donor
management:
1- control bl.p and blood glucose level
2- avoid nephrotoxic drugs
3- match tacrolimus dose with GFR guided by serum creatinine to avoid its nephrotoxicity
4-screen for de novo DSA
5- urine analysis and BK PCR
6- close follow up either clinical visits or laboratory investigations
7- treat according to the cause
yes we can replace tacrolimus by mTor
Fine but GFR is 31
– The renal biopsy arteriolar hyalinosis ,interstital fibrosis and tubular atrophy
DD
CNI toxicity
Age
Chronic GN
DM , HTN
If biopsy was taken early could be
donor age related changes,
if taken at intermediate times could be related to CNI exposure not mandatory to be toxicity
if the biopsy was taken late it could be chronic antibody-mediated rejection and glomerulonephritis and associated lesions.
– management plan
Lower CNI dose with lower trough level
Monitor DSA
Control associated comorbidities as DM ,HTN
1 -mTOR-inhibitor can replace CNI based for this case particularly 1 and 6 months after transplant
to improve renal function ,decrease malignancy risk specially with old age ,and lower CMV infection risk .
2-CNI exposure contributes to the arterial hyalinosis lesions accumulating over time
Donor age correlated with arterial hyalinosis
3-Genetic variation within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body
Implantation biopsy is zero hour biopsy.
So this is quite a recent TX
If any CNI side effect it should be an acute on eg.TMA and not hyalinosis.
Sirolimus is not suitable with the given GFR.
No much information given about the donor apart from the age. Tacrolimus level a bit on the higher side. Type of donation is important DBD versus DCD, cold ischemia time, previous history of AKI, history of comorbidities such as CVD , stroke,HM,HTN,& peripheral vascular disease. The histology shows ;
Differential diagnosis ;
Management plan ; No thing specific here, mostly general management
Can you explain the histological finding in the index case?
What do you think about introducing mTORi?
Arterial hyllanosis may be aging graft and DM
Yes possible to use mTOR
Excellent you correctly mentioned the importance of KDPI index to measure the suitability of the donor and how far can we accept ECD.
Correct to consider low doses of TAC but Sirolimus is not accepted with this GFR.
The given data was inadequate , either the history , investigations& the biopsy . we need more details about the clinical data of the recipient regarding his comorbidities , compliance to medications & the time of the transplant & what about the renal function , did he received dialysis post operatively? .Early posttransplant , the e GFR is not informative so we cannot depends on its level , what was the creatinine trends. The data of the donor was missed , comorbidities ,(DM,HTN ) cause of death ,baseline Cr, any events of hypotension during OR, How was the status of the allograft .The implantation kidney biopsy also was insufficient ,(the status of the glomeruli i.e glomerulosclerosis) any ATN in the biopsy .
The biopsy showed, interstitial fibrosis and tubular atrophy, intratubular casts, arterial hyalinosis.
Deferential diagnosis includes:
1-chronic changes of the allograft ( donor derived).
I could not include CNI toxicity as this was taken during operation before starting TAC.
2- infection UTI ?
The management plan :
it depends on the full data of the recipient , donor, date of operation & the allograft ,Cr trends .
what was the graft function post operatively ?
Need to decrease TAC level if we excluded other factors affecting high level like ,drugs affecting its level , time of taken the tacrolimus .
Provided that all informations are available ,we can proceed for another kidney biopsy if Creatinine not decreasing by 25% from the baseline, or DGF.
Excellent Dr Akram, thank you.
You tackled the missing points in patient’s data
Thanks, Dr Akram
There is no tubular atrophy in the slide. Arteriolar hyalinosis, and interstitial fibrosis are there.
Can you explain the histological finding in the index case?
What do you think about introducing mTORi?
The biopsy was suboptimal showed, interstitial fibrosis and tubular atrophy, intratubular casts, arterial hyalinosis ( severe ). no the glomeruli in the slide.
patient has high level of TAC, although it might be first dose, due to the severe arteriolar hylinosis ( the mechanism of TAC it causes vasospasm of efferent arterioles ) so increase its effects & toxicity .
I think introducing mTORi is better option to avoid the CNI effects on aging allograft . & it is safe even in renal impairment ( low GFR )
The biopsy shows byline arteriosclerosis , cellular infiltrate and tubular atrophy. Since donor was 76 yrs old so it could be because of
Ageing
HTN
DM
His Tac is on higher side , dose of tacrolimus should be reduced
I will keep his Tac on a lowish side as compared to a young recipient
Too short !!
Thank you.
See my questions above
What is the dfferential diagnosis?
This biopsy provided is suboptimal because it does not contain glomerulus so for diagnostic purposes all 4 compartments of the kidney should be present. This micrograph, shows chronic changes: interstitial fibrosis and tubular atrophy, intratubular casts, arterial hyalinosis.
This biopsy taken from donor compatible with Expanded criteria donor given his age, although other cardiovascular risks contribute, like hypertension and diabetes. Baseline kidney function of the donor also is important factor in deciding weather the kidney offer is SCD or ECD,although in this case the age is enough to define ECD.
Differential diagnosis:
-Tacrolimus toxicity could similar picture but it is less likely to be due to CNI, as the biopsy was taken at time of transplantation.
-Chronic changes to to primary diseases of the donor as hypertension , DM and vascular diseases.
-Antibody mediated rejection could give some features of the provided picture but not all in combination however should be part of the initial differential diagnosis.
What is your management plan?
Management plan includes:
kidney biopsy should be repeated as no glomerulus observed in the picture.
This needs to be reviewed
Excellent
See the questions above
Thank you.
Why DSA and C4d?
No need for DSA and C4d staining because the biopsy was taken upon transplantation. so this is time zero biopsy. So DSA and C4d are not needed.
What are the possible diagnoses to consider?
This equals a donor kidney pathology that may be related to old age or due to other chronic donor illnesses(DM, HTN, age-related; this kidney offer is known as a Marginal donor or ECD kidney offer. The renal biopsy is revealing interstitial fibrosis and vascular hyalinosis, which is also evident in the implantation biopsy.
Patients older than 60 years old, patients with a history of hypertension, patients who passed away as a result of a cerebrovascular stroke, and patients with an increased blood creatinine level are all considered to have ECD.
This patient is considered an ECD. I would like to know the medical history of the donor and the base creatinine before donation and whether the donor is brain dead or post-cardiac arrest.
tacrolimus level is high, I will keep the tacrolimus on the lower limit of the target. early post-transplant around 8 is accepted. routine medical care for chronic kidney disease, including ideal blood pressure control, blood sugar control, hyperuricemia control, and preventing further kidney damage by avoiding drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs). Antihypertensive agents (ACEI or ARB), oral hypoglycemic agents or insulin, and urate-lowering therapy (allopurinol/febuxostat) were prescribed according to each patient’s clinical status.
Thank you
See the questions above
The implantation biopsy revealed the presence of arteriolar hyalinosis. renal tubular atrophy, interstitial fibrosis with cellular interstitial infiltrate. Differential diagnosis:
aging { as the donor is 76 year old}
Hypertension. with hypertensive nephropathy.
Diabetic nephropathy.
Chronic Interstitial Nephritis with IFTA.
This kind of unhealthy allograft is utelized to expand the donors pool.
His eGFR is only 31ml/min.and his Tacrolimus level is 14 ng/ml, which is a toxic level as well.
plan:
To minimize CNI exposure.
mTor might be of benefit in halting the Interstitial fibrosis.
RAAS inhibitors are helpful in this situation as well.
Thank you.
Can we use mTORi in the index case?
The biopsy show interstitial fibrosis and arteriolar hyalinosis , no glomeruli are present in this section
DD of arteriolar hyalinosis
1- advanced donor age
2- DM
3- HPN
4- CNI nephrotoxicity
5- AMR
6-Vascular diseases
7- prolonged ischemia time.
Management plan :
1- To identify the cause of AH in this case more data about the donor is required as if he was diabetic , hypertensive , any vascular diseases , cause of death and cold ischemia time . he may be an ECD .
2- Decrease the dose of CNI to maintain through level at low therabutic borders as this is a low risk transplantation . If no improvement in kidney function after that , consider CNI miniming protocol or CNI free protocol with shift to either m TOR or belatacept.
3- Control diabetes , hypertension if present
4- Monirtoring of DSA.
5- C4 d stating of renal biopsy
Thank you.
Why DSA and C4d?
The section of graft biopsy ( H&E stain) shows arterial hyalinosis & IFTA.
Differential diagnosis:
Management:
References:
Thank you.
Can we use mTORi in the index case?
mTORi can be used when GFR > 40, so in this patient we can’t
The slide show
H&E stain showing interstitial fibrosis and arterial hyalinosis
arteriolar hyalinosis (ah) in kidneys has complex associations with :-
1-renal aging
Donor age is the major determinant for the presence of arteriolar lesions early in the course after transplantation.
2-hypertension
3-diabetes
4-progressive renal diseases
5-calcineurin inhibitor (CNI) immunosuppressive drugs
6-AMR
Arteriolar hyalinosis in kidney transplants is considered the histopathologic hallmark of chronic calcineurin inhibitor (CNI) toxicity.
However, the late biopsy samples from patients not receiving CNI therapy more frequently dem- onstrated arteriolar lesions, and time since transplantation was significantly longer.
Thus, AH is apparently a function of time after transplantation, without specific or exclusive relation to hypertensive or diabetic vascular damage or to CNI toxicity. It may be the result of cumulative burden of vascular injury to the allograft.
Treatment
1-control on HT,DM and dyslipidemia
2-monitor for proteinurea
3- graft function
4-Close monitoring with DSAs level
5-CNI minimizing dose protocol or CNI free protocol
((Use MMF and Steroid))
Sirolimus if GFR >40ml/min
Reference
1-Verena Bröcker,* Victoria Schubert,*
Irina Scheffner,† Anke Schwarz,† Marcus Hiss,† Jan Ulrich Becker,* Ralph Scherer,‡
Hermann Haller,† Hans Heinrich Kreipe,*
Michael Mengel,§ and Wilfried Gwinner†.
Arteriolar Lesions in Renal Transplant Biopsies
Prevalence, Progression, and Clinical Significance.
The American Journal of Pathology, Vol. 180, No. 5, May 2012 Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc.
DOI: 10.1016/j.ajpath.2012.01.038..
2- Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation
G. Einecke, J. Reeve, P. F. Halloran
First published: 22 November 2016
https://doi.org/10.1111/ajt.14136
Citations: 23
Well done
Thank you.
Did you mention AMR, in your differential diagnosis?
Can you explain this please
Chronic allograft rejection can be caused by antibody-dependent complement activation lesions as well as cell arteritis leading to the development of interstitial fibrosis/tubular atrophy (IF/TA).
This injury can appear early after transplantation. At 1-year post-transplant, greater than 81% of the kidneys have minimal lesions of IF/TA that tend to progress over time; these lesions affect greater than 50% of transplanted kidneys with severe lesions at five years.
Reference
Justiz Vaillant AA, Mohseni M. Chronic Transplantation Rejection. [Updated 2022 Apr 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-
I think the clinical data here is not conclusive.
First of all we need more information about .
a-ABO compatibility.
b-past medical history of the donor and recipient/cause of death.
3-Adequte renal biopsy and IF.
What is the deferential diagnosis?
L/M of renal biopsy which is overall not adequate didn’t revealed glomerulus but showing interstitial fibrosis with tubular atrophy and mainly tubular and arteriolar haylonosis(hyaline homogenous material in tubules and arteriolar wall).
1-Mainly in this situation may previous lesion in donor (HTN and DM or chronic kidney injury) or reduced nephron mass due to donor age which may be offer as a marginal donor (ECD).(specially as the biopsy is on table post-transplant).
2-CNI toxicity specially with high Tacrolimus level 14 which should be (target CNI blood levels 25%-50% lower) than usual in ECD.(1)
-Which is called an arteriole with severe tacrolimus-associated hyalinosis(2).
3–Feature has also been described in donor-transmitted nephrosclerosis and in patients dying of ischemic cardiomyopathy.(2
What is your management plan?
1-To adjust tacrolimus level by decreasing tacrolimus dose.
2-To control recipient metabolic diseases (HTN/DM & Dyslipidemia).
3- CNI -free Belatacept-based protocol.
4-Reduced CNI exposure and CNI-free mTOR-inhibitors-based regimens.
References:
1-Filiopoulos, Vassilis, and John N Boletis. “Renal transplantation with expanded criteria donors: Which is the optimal immunosuppression?.” World journal of transplantation vol. 6,1 (2016): 103-14. doi:10.5500/wjt.v6.i1.103.
2-Randhawa, Parmjeet S et al. “Tacrolimus (FK506)-Associated Renal Pathology.” Advances in anatomic pathology vol. 4,4 (1997): 265-276. doi:10.1097/00125480-199707000-00032.
Excellent inquiry about the donor
Notice that it is a weak or 10 days post tx.
This is a zero hour biopsy
What is donor transmitted nephro sclerosis do you mean donor nephro sclerosis.
Sirolimus is not suitable with this GFR
But we’ll done
Thank you.
You mentioned sirolimus as one of the treatment options. Do you think it is appropriate in a patient with eGFR 31 mls/min?
LM:
shows IF/TA AND ARTERIAL hyalinosis.
There IS thrombotic microangiopathy.
DD:
CNI toxicity.
CABMR.
Hypertension.
DM.
TMA.
Chronic CNI toxicity:
· Hypertension and slow progression to renal failure.
· Arterioles show hyalinosis of vessel walls or mucoid
thickening of intima, leading to luminal narrowing
· Also diffuse interstitial fibrosis and tubular atrophy
·
Monitoring of CNI trough level. reduce the dosage.
Control of BP and Diabetes.
Consider the donor this is zero hour biopsy
Too early for chronic CNI toxicity
What are the questions to be asked about the 67 years old donor.
If hypertensive , diabetes Or not .i.e ECD.
Thank you.
Did you mention CNI toxicity and TMA? How would you explain this differential diagnosis?
Light microscopy, H&E stain showing interstitial fibrosis and arterial hyalinosis.( There is thickening of the walls of arterioles by homogeneous pink hyaline material.)In this case hyalinosis is likely because of donor factors. This kidney offer is referred to as a Marginal donor or ECD
What is the differential diagnosis?
1-Donor disease/age -donor’s medical history ( DM, HTN), cause of death ( vascular disease) and GFR at the time of death .Donor’s Pathology like Glomerulosclerosis , interstitial fibrosis, hypertensive vascular changes, and thrombotic microangiopathy should be considered.
2-Other points in the history like cold ischemia time, any history of rejection, DSA status, any history of infection, recurrent disease should be considered .
3- CNI toxicity-if exact time of biopsy taken known.
What is your management plan?
Close monitoring of CNI level and adjusting accordingly (keeping it at the lower level in this case because of low immunological risk)
Control of BP and DM if there is any history.
Follow up graft function and monitor for dyslipidemia and proteinuria .
Modification of IS protocol-CNI withdrawal or minimization
REFERENCE:
1-Einecke G, Reeve J, Halloran PF. Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation. American Journal of Transplantation 2017; 17: 1346–1357
Excellent observational inquiry of Tac level and later plan to avoid CNI but what is the suggested alternative?
Thank you.
What is the differential diagnosis?
What is your management plan?
1- Reduce tacrolimus dose because of the following :
2- Optimize volume state
Excellent explanation of ECD
Can you elaborate more on immunosenesence
Any suggestions for Tac level with this dose and duration?!
Immunosenescence means that the immune system becomes weak with aging so there is a lower risk of rejection in elderly individuals and higher risk of infection and malignancy
Low dose of tacrolimus producing a high tac level can be explained by the following :
LM shows typical lesion of arteriolar hyalinosis in D0 which is likely
Donor related arteriolar hyalinosis (ECD, old donor above 70 years )
Donor comorbid diseases like DM, HTN with associated risk of chronic vascular changes and arteriolar hyalinosis
prolong cold ischemia time (DD with ECD), ischemic reperfusion injury in addition the
use of CNI can worsening the condition and aggravate the risk of DGF, and acute CNI toxicity. There is good evidence of the efficacy of mTOR I in preserving the transplanted kidney function among standard risk renal transplant recipients, with a graft survival equivalent to other conventional immunosuppressant protocols (1)
in this case induction as standard immunological risk with basiliximab but from ECD,(DD) and increase risk of DGF especially i if DCD with prolong cold ischemia time and early use of CNI, Preferred to use CNI minimizing dose protocol with MMF and steroid and early introduction of sirolimus or everolimus or CNI sparing protocol with everolimus ,MMF and steriod in the first two months .
Close monitoring with DSAs level , graft function ,proteinuria and drugs level monitoring
Screen for infection including surgical wound infection, lymphocele with the early use of m TOR i
Better BP and sugar control, monitor for dyslipidemia and proteinuria with m TOR i
References:
1-m-TOR Inhibitors in Kidney Transplantation: A Comprehensive Review Mekki M1,2, Bridson JM2, Sharma A2,3 and Halawa A2,4, J Kidney 2017, 3:3 DOI: 10.4172/2472-1220.1000146
2– Ekberg H, Silva HT, Demirbas A, Vítko S, Nashan B, et al. (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. NEngl J Med 357: 2562-2575.
3-Mühlbacher F, Neumayer HH, Castillo D, Stefoni S, Zygmunt AJ, et al. (2014) The efficacy and safety of CyA reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: Results from an open Label comparative study. Transpl Int 27: 176-186.
4- Bechstein WO, Paczek L, Wramner L, Squifet JP, Zygmunt AJ, et al. (2013) A comparative, randomized trial of concentration-controlled sirolimus combined with reduced-dose tacrolimus or standard-dose tacrolimus in renal allograft recipients. Transplant Proc 45: 2133-2140.
5- Uchida J, Machida Y, Iwai T, Kuwabara N, Kabei K, et al. (2014) Conversion of stable ABO-incompatible kidney transplant recipients from mycophenolate mofetil with standard exposure calcineurin inhibitors (CNIs) to everolimus with very low exposure CNIs-a short-term pilot study. Clin Transplant 28: 80-87
Excellent
Tac level with this dose and duration what are the possibilities?
Sirolimus with GFR 31?,
ECD to eldelry patient with assumed standrad immunological risk with immunosensce in old recipient ( low immune response and requering less aggressive IS , he had vascular changes related to the aging or previous vascular disease that put him at risk of CNI toxicity so his currnet dose of tacrolimus can fruther adjusted to lower target of 6-8ng and continue same dose of MMF and tapper dose of steriod with close monitoring with GFR level , tacrolimus trough level and protienuria also once his GFR improved above 40ml/min with no protineuria can consider shifting to CNI sparing protocol orCNI minimazation protocal with m TOR inhibitors
also in old age recipients we should take in consideration in addition to the decreased immune response they also at risk of CNI toxicity due toaltered pharmacokinetics espcially with CNIs due to reduced cytochrome P450 activity that put them at risk of CNI toxicity, so they need modifciation of immunsuppression with lower dosing as compared to youner recpinets, so in this case we can keep him on MMF and steriod manitenace IS and once GFR fruther imporved above 40 ml/min with no protineuria can consider addition of m TOR inhibitors, also address the assocaited comorbid diseases including cardiovascular , peripheral vascular disease , BP and DM control as all ca impact both the graft and patinet survival.
REFERENCES :
1-Age and immune response in organ transplantation.Martins PN, Pratschke J, Pascher A, Fritsche L, Frei U, Neuhaus P, Tullius SG
Transplantation. 2005;79(2):127.
2-European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.12. Elderly (specific problems).EBPG Expert Group on Renal Transplantation
Nephrol Dial Transplant. 2002;17 Suppl 4:58.
What is the deferential diagnosis?
This renal biopsy, taken at the time of implantation of an aged deceased donor kidney, shows hyaline arteriolo-sclerosis.
There is thickening of the walls of arterioles by homogeneous pink hyaline material.
Here the cause of arteriolosclerosis is likely due to aging process (donor age was 76 years).
Arteriolar hyalinosis occurring in early transplant
renal biopsy is most likely due to a preexisting
donor factors
Other donor factors associated with arterial sclerosis are:
– Hypertension
– Diabetes mellitus
– Drugs: calcineurin inhibitors (unlikely in this case, biopsy taken at the time
of implantation)
What is your management plan?
– Good blood pressure control in recipient
– Good glycemic control
– Optimize tacrolimus dose: keep trough level at lower range of normal
– Consider CNI withdrawal or minimization
Reference
Bröcker et al. Arteriolar Lesions in Renal Transplants 1853
AJP May 2012, Vol. 180, No. 5
Excellent
But if Tac level is high with this dose and duration what are the possibilities and what would be the expected lesion?
Well done
Thanks a lot dear Prof. Dawlat
Increasing recipient age affects TAC pharmacokinetics, with higher TAC seen in older patients.
I would ask for concomitant medication that increase tacrolimus drug level by inhibiting cytochrome enzymes.
Higher trough level early post-transplant are associated with less acute rejection rates.
Increasing recipient age affects TAC pharmacokinetics, with higher TAC seen in older patients.
I would ask for concomitant medication that increase tacrolimus drug level by inhibiting cytochrome enzymes.
Higher trough level early post-transplant are associated with less acute rejection rates.
O’Seaghdha CM et al. Higher tacrolimus trough levels on days 2–5
post-renal transplant are associated with
reduced rates of acute rejectionClin Transplant 2009: 23: 462–468 DOI: 10.1111/j.1399-0012.2009.01021.x
In the current scenario:
Renal transplant recipient 61 years old from deceased donor 76 years old with 110 HLA mismatch with induction of immunosuppression as a standard immunologic risk with no proteinuria, Graft dysfunction (GFR of 31 ml/min) and high Tacrolimus level.
Basically, the scenario is confusing ; is it implantation biopsy (means at the time of transplantation) or it is post-transplant biopsy (because usually Tacrolimus is not commenced directly post-transplant except after documented graft function)?
Implantation biopsy revealed:
Light microscopy,H&E stain showing no glomeruli, Tubules not back to back with apparent interstitial fibrosis. The picture showing arterial hyalinosis.
What is the deferential diagnosis?
DD of arterial hyalinosis in early post-transplant time:
1-Donor pathology as Glomerulosclerosis , interstitial fibrosis, hypertensive vascular changes, and thrombotic microangiopathy TMA may be present in marginal donors.
2-Consider the possibility of active AMR with evidence of acute tissue injury in the form of TMA
3-In view of high Tacrolimus level if it is post-transplant biopsy we can consider CNI toxicity.
What is your management plan?
Management plan requires a good transplant history regarding :
-Past medical history of the deceased donor:DM,HTN,cause of death
-Terminal creatinine and GFR before procurement
-Recipient PRA,DSA levels if any and cross match result>>From the slandered induction it gives idea regarding DSA level and cross match.
-Cold and warm ischemia times.
Close monitoring of CNI level and adjusting accordingly ,control of BP and DM if any. Follow up graft function and re biopsy if more worsening of creatinine.
Excellent explanation and analysis of the given information
It is a zero hour biopsy so whatever chronic lesions belong to the donor so donor information immediately before Tx is mandatory.
Why is Tac level so high with this dose and in such a short time and if so what type of lesion would it cause?
Well done.
Thank you Prof. Dawlat,
Concomitant use of some medications can increase Tacrolimus level as antibiotics like clarithromycin, erythromycin and antifungal as fluconazole.
Calcium channel blockers as Nifedipine
-High Tacrolimus level can cause acute CNI toxicity caused by affecting graft hemodynamic through acute afferent arteriole vasoconstriction and causing tubular isometric vacuolization.
The implantation biopsy showed the presence of arterial hyalinosis.
I put this differential diagnosis:
For the first differential diagnosis, I need to know the donor’s medical history ( DM, HT), cause of death ( vascular disease) and terminal GFR. keeping in mind the donor is 76 years old.
For the second DD: I need to know the time post-transplant at which this Tac level was done and any other features of CNI toxicity.
For the third DD: I need to get further information like the time post-transplant, primary function, cold ischemia time, any history of rejection, DSA status, any history of infection, recurrent disease, and proper biopsy to show any evidence of IFTA and glomerular sclerosis.
What I understand from the given history is this patient was transplanted from an old deceased donor ( ?? ECD), the graft at the time of implantation already showed hyalinosis, no information about the donor creatinine at the time of implantation, and the recipient received Tac based IS with high Tac level ( don’t think the recipient is in need for this high level given his age and the degree of mismatching) that is unfit for the graft status with resultant deterioration in graft function.
Reference:
Excellent that you notice the discrepancy of the information!
You are right about the donor’ pretransplant chemistry.
Remember this is a zero hour biopsy.
Your diffential diagnosis is correct apart from CNI toxicity .
Management plan is very good
Thank you,,,
Yes, I know that it is an implantation biopsy, My diagnosis diagnosis of Tac toxicity is not based on the biopsy findings at the time of implantation, but because of the low GFR and high Tac level for a patient who is 61 years old and a graft with high degree of hyalinosis at time of implantation which is mostly due to the donor’s age +- comorbidities
1. Since it is an aged kidney, can we give mTORi?
indications for mtori are –
Preferably for low immunological risk recipients
completely healed wounds
a negative protocol biopsy
no proteinuria
little risk of recurrent disease (ie, primary focal segmental glomerulosclerosis)
no donor-specific antibody
demonstrated tolerance of antiproliferative agents and steroids
conversion is done after 3 to 6 months run in period with a CNI/antiproliferative agent/P .
target Co of SRL 8 to 12 ng/mL or EVL 3-8 ng/mL.
no dose adjustment is needed according to gfr.
reference- sirolimus drug insert
2. What is the difference between hyalinosis of ageing and hyalinosis of CNI toxicity?
The histologic changes in aging include –
hyperplastic elastic arteriosclerosis present in the interlobular arteries
intimal thickening
reduplication of the lamina elastica interna
mild hyalinization
The histologic changes in chronic CNI toxicity –
Arteriolar hyalinosis (nodular hyaline deposits in the media of afferent arterioles) is a hallmark of CNI nephrotoxicity and is defined by the replacement of necrotic smooth muscle cells by localised or circular lumpy protein (hyaline) deposits at the periphery of the afferent arteriole wall. These nodular hyaline deposits eventually grow to the point where they constrict the arterial lumen.
Striped interstitial fibrosis.
So in aging in addition to arteriolar hyalinosis reduplication of lamina elastic internal and hyper elastic arteriosclerosis is seen mainly in interlobular arteries while CNI toxicity nodular hyalinosis is seen mainly seen in afferent arterioles.
3. Can you explain the high Tac level while this patient receives only 1mg BD?
Tacrolimus is predominantly metabolised in the gut wall and liver by cytochrome P450 (CYP) 3A enzymes. P-glycoprotein, which counter-transports dispersed tacrolimus out of intestinal cells and back into the gut lumen, uses it as a substrate. The pharmacokinetics of tacrolimus in the elderly would be predicted to be affected by age-related changes in-
CYP 3A and P-glycoprotein expression and/or activity
changes in liver mass and body composition.
Also any drug interaction needs to be ruled out .
Liver function tests to be done
biopsy shows interstitial fibrosis and hyalinosis of vessels.
d/d
age related
diabetes
hypertension
basiliximab or ATG induction with CNI minimisation with or without steroid withdrawal