2. A 61-year-old male patient with old CKD 5 received a deceased donor kidney (34-year-old) 17 years ago, 101 mismatch, received basiliximab induction, triple immunosuppression (tacrolimus 3 mg BD, MMF 500 mg BD and prednisone 5 mg OD). His eGFR is 17 ml/min and there was no proteinuria. Tacrolimus level is 9.1 ng/ml. His recent biopsy is shown below:
- What is the deferential diagnosis?
- What is your management plan?
Dear All
How often do you
get DSA, POSITIVE C4d proteinuria in cases of chronic allograft injury?
In fact , its commonly encountered, with a diagnosis of chronic active AMR, in which the patients usually presented with chronic deterioration of allograft function and protinuria.
Thank you Wael, but you have not answered the question
Im not sure about DSAs, but its common to have C4d positive chronic active AMR in the daily practice. Proteinuria is commonly encountered as well, but its ofter absent in some cases.
I think it depends on the site and the cause of allograft injury.
The causes of chronic allograft injury are divided into:
The potential sites for injury are:
So, not all the causes of chronic allograft injury and/or the sites of the injury will lead to the combination of positive DSA, proteinuria, and positive C4d staining.
Reference:
Langewisch E, Mannon RB. Chronic Allograft Injury. CJASN. 2021 Nov; 16.
Excellent
thank you
Excellent Huda
thank you
We do get it especially when it is labeled as chronic active antibody rejection .
in may littl practice , i had never seen it .but it can happen in ABOi transplantion with positive histroy of DSA befor transplantion and devloping AMBR .
You may get this up to 40 to 50% of cases
Banff 2003 mention that presence of c4d change should taken as chronic humoral rejection
the most allograft are lost by chronic antibody -mediated rejection that is consequence of de novo development of DSA .every year about 4% of kidney graft are lost
20% at 10 years incidence of de novo DSA associated with graft dysfunction and proteinuria
references
handbook of kidney transplantation
comprehensive nephrology
DSA is the cause for TG in about 80% of patients.
Positive staining of C4d (Banff scored C4d ≥ 1) in 22.6%.
Proteinuria ≥1 g/24 h at the time of biopsy was detected 46.8%.
(A retrospective cohort analysis of 186 TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival).
Reference
Qiang Zhang et al. The relationship between proteinuria and allograft survival in patients with transplant glomerulopathy: a retrospective single-center cohort study. Transplant International 2021; 34: 259–271
in 48.8%
chronic allograft injury is caused by immunological and nonimmunological causes so once its cause-related to chronic ABMR c4d and DSA will be +ve otherwise DSA and c4d will be -ve
Chronic allograft nephropathy ( now, called transplant glomerulopathy) is an example of immune mediated chronic graft damage, either TCMR or ABMR, in which DSA can be detected in nearly 80% of cases, c4d in nearly 40% and significant proteinuria detected in nearly half of cases.
when the underlying of CAI is chronic ABMR, then C4d and positive DSA may be encountered.
Chronic allograft injury either immun- mediated or non
Immunomediated occured with infection where non- immunomediated occured with CNI toxicity
What is the deferential diagnosis?
1)Chronic allograft rejection. ABMR, TCMR.
2) CNI toxicity.
3) BKV Viraemia.
What is your management plan?
DSA , FK level,BKV PCR, C4d staining
Adjust immunosuppressant according to blood TDM level.
IV hydration
Serial renal profile and DSA
The slides show interstitial fibrosis with tubular atrophy,arterial hylinosis and double basement membrane all goes with chronic allograft nephropathy mainly due to chronic antibody mediated rejection .
Mangment will start by adjusting the dose of prograf to avoid more histological changes of CNI toxicity then check for circulating DSA and did C4d stain to know if there’s chronic active antibody mediated rejection .
Taking the fact of this low GFR with this chronic changes in the biopsy ;I will follow him as CKD patient
Picture of chronic allograft injury
D/D
It’s may be immune mediated due to DSA
Infection like BK virus
recurrence of glomerular disease
or non immune disease due to calcinurine inhibitors ( this most likely because high level of drug
Non adherence to immunosuppressive agents
non compliance
Management are good history and control blood pressure and sugar
drug level and adjustment of calcinurine inhibitors dose
DSA level
consider dialysis and retransplant
Slide 1 from the left side: shows interstitial fibrosis and tubular atrophy
Slide 2 in the middle shows arterial hyalinosis
Slide 3 shows PAS stain with thickened basement membrane, atrophic tubules and interstitial cellular fibrosis
So the DD:
– IFTA; CAN
– Chronic mixed rejection
– BK virus
– Check drug level
– C4d staining
– BK viral investigation
– Adjust the dose of IS medications
– Control of bp
– If IFTA most likely so prepare the patient for dialysis or put him on the list of second transplant
Biopsy findings are thickening and hyalinosis of medium layer of the blood vessels which may reflect aging process or hypertensive changes beside rejection. There is dominant interstitial lymphocytic infiltrate with interstitial edema and vacuolation of tubules. The PTC showed thickening of the basement membrane and
Differential diagnosis :
Plan of management:
Glomeruli: non
Left slide: IF, tubular atrophy, stripped fibrosis.
Middle slide: Hyalinosis
Right slide: PTCs C4d staining.
DD: CNI toxicity, Hypertensive changes, chronic allograft nephropathy, chronic rejection, BK nephropathy
Reduce dose of Tacrolimus, aim for level 3-5 ng/ml
Check DSA , BK virus.
Control other comorbidities as BP, DM
Advanced kidney care follow up for second transplant or renal replacement therapy.
1. Here is our patient, who had a graft from deceased donor, 17 years ago, presented with rising creat, GFR 17 ml/min with the provided micrographs showing evidence of chronic graft damage as :
_ slide one shows interstitial fibrosis and tubular atrophy and collapse.
– slide 2 shows arterial hyalinosis , thickening and multi layering of the wall.
– slide 3, stained by silver stain showing atrophy of tubules, irregular basement membrane and double contour.
-hence, the differential diagnosis of chronic allograft nephropathy (CAN) or transplant glomerulopathy either:
– chronic active ABMR or TCMR
-CNI toxicity .
-Uncontrolled systemic disease as diabetes or hypertension.
– BK nephropathy or CMV infection.
2. Management plan should include extensive search for the etiology and proper management .
– circulating DSA and c4d staining to exclude chronic ABMR.
-decoy cells in urine for BK nephropathy.
– CMV and BK virus PCR.
-follow up ABP and it’s control.
-random blood glucose, HBA1C .
The appropriate management -will be
a- ensure adequate fluid intake to prevent pre renal renal failure.
b- avoid nephrotoxic medications that can add to the problem
c. Adjust tacrolimus trough level, as 17 years post transplant does not require trough level of 9, level around 5 will be quite sufficient.
-shift from CNI to m TOR is recommended by the KDIGO to minimized CNI induced nephrotoxicity, but it can not be done here as GFR less than 40 ml/min is contraindication to use of sirolimus. So lowering dose of CNI will be the most appropriate here.
d. Exclude BK by PCR and special stain, SV 40 of graft biopsy, and give ttt accordingly.
e. Control blood glucose and arterial blood pressure to prevent or delay progression to ESKD.
-treatment of chronic rejection is still a matter of debate.
F. By the end of the day, it is mostly chronic and irreversible changes, so planning for RRT as dialysis or retransplantation should be offered to our patient.
g- conservative management is the same for CKD as managemnt of anemia with ESA and management of CKD-BMD by supplementation of active vit D and phosphate binders.
Biopsy findings are those of chronic allograft Injury which might be caused by :
.Chronic rejection
. recurrent / chronic glomerular disease ( although no glomerlui are seen !)
. CNI nephrotoxicity
, BK virus nephropathy
Management plan ?
elicit Hx of prior renal disease , DGF after transplantattion , rejection episodes
check DSA
urinalysis to look for evidence of glomerular disease ( cellular cast )
adjust TAC dose for a trough level of 3-7 ng/ml
BK workup ( PCR , SV 40 stain for biopsy) , and reduce immunesuppression accordingly
control blood pressure, glucose and lipids
arrange for RRT ( dialysis and later on to consider a second transplantation
As far as professor Ahmed Halawa question…proteinuria will be present if there is significant injury to the glomerulus in the form of GBM thickening and multilayering with glomerulitis If the Chronic allograft injury is predominantly in the tubular or the blood vessels significant proteinuria will not be there
*What is the differential diagnosis?
Renal biopsy slides describes changes of chronic transplant glomerulopathy .
Where there is interstitial inflammation and fibrosis ,Arterial multilayer, tubuls shows thicking of basement membrane,wrinkling and atrophic tubules.
Causes of chronic allograft dysfunction:
*CAMR,BK nephropathy.
*associated chronic disease as Diabetes ,hypertension or urinary tract infection .
*CNI toxicity
What is your management plan?
Mange as CKD patient
-Control of associated medical conditions
DM,HTN ,UTI.
– low protein diet
-avoid nephrotoxic agents.
– DSA level .
-Screen for CMV and Bk viruses .
-decrease tacrolimus dose to trough level 5 ng/ml.
-Counselling the patient about retransplantation or dialysis
Type
Chronic allograft dysfunction,
basement membrane duplication, hyalinosis and arterial wall thickening may be caused by chronic antibody mediated rejection, CNI nephrotoxicity, DM and HTN
Interstitial fibrosis and tubular atrophy, may be due to BK nephropathy, recurrent UTI, urinary tract obstruction or CNI nephrotoxicity
Minimization of modifiable risk factors as no definitive treatment is available, optimization of immunosuppression with adjustment of Tacrolimus level to keep it (5-7ng/mL).
Strict control of blood pressure, adequate glycemic control and correction of hyperuricemia
screening for viral infection (BK virus and CMV)
Arrange for vascular access to start dialysis when needed as the eGFR is 17ml/min.
Langewisch E, Mannon RB. Chronic Allograft Injury. Clinical Journal of the American Society of Nephrology. 2021 Nov 1;16(11):1723-9.
Pascual J, Pérez-Sáez MJ, Mir M, Crespo M. Chronic renal allograft injury: early Detection, accurate diagnosis and management. Transplantation Reviews. 2012 Oct 1;26(4):280-90.
Pictures shows
Slide 1 shows interstitial inflammation and tubular atrophy
Slide 2 shows arterial hyalinosis and multilayering
Slide 3 shows silver staining of tubular wrinkling and thickening of basement membrane
The biopsy is not sufficient but the most probable diagnosis after consideration of patient hx of 17y post-transplantation is chronic allograft injury caused by
-immunological causes (TCMR, ABMR, recurrence of 1ry GN and infection)
-non-immunological (CNI toxicity, DM, HTN, and obstructive uropathy)
The management at this advanced stage
we should look at the trend of his GFR as this biopsy is not sufficient which may lead to sampling error
1. if he has stable graft function and stable GFR around 17ml/min the best management is
· good hydration
· avoid any nephrotoxic drugs
· control of all risk factors can cause more rapid deterioration of kidney function like DM.HTN
· decrease tac level targeting level around 5ng/l
· control of advanced ckd complications like CKD-MBD and anemia
· prepare patient for RRT modality after patient counseling about his 3 options (HD,PD, and kidney tx again)
· low protein low salt diet
2. if the patient has unexplained rapid deterioration of his GFR we should look for the cause
· -ultrasound to exclude post-renal causes in such age like BPH
· -DSA screening
· -virology screening for CMV and BK
· -may be another biopsy should be considered
· -decrease tac level to be around 5
The provisional diagnosis would be:
Chronic allograft nephropathy (causes may be due chronic AMR, CNI toxicity)
Based on the data provided of this male 61 yr. old, RTx 17 years ago, high CNI level FK 9.1, low GFR 17 mLlmin, and the biopsy showing:
Interstitial lymphocytic infiltrates, IFTA interstitial fibrosis and tubular atrophy,
Thickened arteriolar wall, arteriolar hyalinosis,
Vacuolization, C4D deposits, and lymphocytic infiltration (PAS stain).
So, it is a combination of both chronic ABMR and CNI toxicity.
While other reasons could be possible differential diagnosis (BK nephropathy, medical diseases as DM, HTN)
Management plan:
Triple immunosuppression would be the same with dose modification according to drug level (better to keep FK level round 4 or 5), body weight and estimated GFR.
Attention to any co morbidities including DM, HTN or benign prostatic enlargement and controlling them as much as possible.
Ensuring patient’s adherence to all medications.
Screening for CMV, and BK viruses.
Screening for DSA (for the current situation and future retransplantation option).
Close follow up is needed with special regards to renal functions , and proper counselling of the patient about options of RRT renal replacement therapy either the need of dialysis , establishment of vascular access or proceeding for renal transplantation and enrolling in kidney transplantation programs.
Improvement of CKD associated symptoms as anemia, gastritis, anorexia, and bone mineral disease.
References[1]
J. Pascual, A. Alonso, D. Burgos, J.M. Cruzado, D. Seron
Grupo Español de Consenso sobre disfunción renal crónica en pacientes trasplantados renales. Chronic renal dysfunction in kidney transplant recipients. Consensus document
Nefrologia, 32 (Suppl. 2) (2012), pp. 1-28
Google Scholar
[2]
K. Solez, R.B. Colvin, L.C. Racusen, et al.
Banff ¨05 meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (CAI)
The images show light microscopic kidney biopsy pictures from a deceased donor kidney transplanted 17 years ago now presenting with low GFR (17 ml/min) and a tacrolimus level of 9.1 ng/ml.
Slide 1: H& E stain showing Interstitial fibrosis
Slide 2: Showing arterial wall thickening
Slide 3: PAS stain showing Tubular atrophy with wrinkling and thickened basement membrane surrounded by cellular infiltrates.
Both clinical picture and the kidney biopsy taken together, even in absence of a glomerulus and C4d staining, it points towards chronic allograft injury.
The causes of chronic allograft injury include both immunological and non-immunological causes. Immunological causes include rejection (both cellular and antibody mediated), recurrence of the basic glomerular disease, infections like recurrent UTI, CMV and BK virus. Non-immunological causes include CNI nephrotoxicity, diabetes mellitus, hypertension, pre-transplant donor factors including age of donor, extended criteria donor, ischemia reperfusion injury, ureteral obstruction and renal artery stenosis.(1,2)
This patient is having eGFR of 17 ml/min with Tac level 9.1 ng/ml
Diagnostic evaluation includes:
1) History regarding rejection, adherence, blood pressure, diabetes and any infection
2) An adequate biopsy including C4d staining
3) USG graft kidney with Doppler
4) CMV and BK virus PCR
5) DSA levels
Treatment involves:
1) Reducing the tacrolimus dose to decrease the trough tacrolimus level
2) Control of BP and blood sugars
3) Treatment of infections, if any
4) Counselling the patient and family members regarding the graft prognosis, preparation for RRT in form of AV fistula creation and looking for a prospective living donor in the family.
5) Evaluation and management of other complications associated with low GFR including anemia and bone mineral disorders.
References:
1) Langewisch E, Mannon RB. Chronic Allograft Injury. Clin J Am Soc Nephrol. 2021 Nov;16(11):1723-1729. doi: 10.2215/CJN.15590920. Epub 2021 Apr 5. PMID: 33820759; PMCID: PMC8729407.
2) Riella LV, Djamali A, Pascual J. Chronic allograft injury: Mechanisms and potential treatment targets. Transplant Rev (Orlando). 2017 Jan;31(1):1-9. doi: 10.1016/j.trre.2016.10.005. Epub 2016 Oct 11. PMID: 27847221.
This slides shows interstitial fibrosis and tubular atrophy, it’s may consider chronic allograft rejection
Calcinurine inhibitors toxicity
Management monitoring tacrolimus level and reduce dose
DSA level
plain for C4d staining in renal biopsy
consider dialysis because eGFR less than 17ml/min
What is your differential diagnosis?
Picture 1- Intimal Fibrosis/ Tubular atrrophy
Picture 2- Arterial multilayering
Picture 3- Tubular atrophy , interstitial and intimal fibrosis
Causes can be —
CNI toxicity
Chronic rejection
BK nephropathy
UTI, Obstruction ,reflux
Medical conditions like diabetes , hypertension
What is your management plan?
Counselling the patient about situation
Check CNI levels and optimize
Control medical conditions
Avoid nephrotoxics
Check DSA and BK virus
Treat UTI if detected
Discussion about possible change in situation in near future and need for dialysis , Vascular access and retransplant.
What is the differential diagnosis?
Picture 1-tubulitis and inflammatory cells infiltration
Picture 2- intimal fibrosis with concentric re-duplication of intima
Picture 3- Tubular atrophy, interstitial fibrosis, and arterial intimal fibrosis
Differential diagnosis
CNI nephrotoxity
ABMR
Chronic allograft rejection
BK virus nephropathy
Hypertension, Diabetes mellitus, dyslipidemia
What is your management?
Reduce tacrolimus levels to around 5-6
Serial measurements of serum creatinine and proteinuria.
DSA measurement and monitoring
C4d staining
screening for viral infection, especially BK virus. Treat viral infection if needed
Most likely the progression of allograft failure is inevitable
Counsel patient about future need of dialysis and start donor workout for retransplantation.
References
Chronic Allograft Nephropathy
Agnes Fogo, MD
DOI:https://doi.org/10.1053/S0272-6386(13)90051-2
Langewisch E, Mannon RB. Chronic Allograft Injury. Clin J Am Soc Nephrol. 2021 Nov;16(11):1723-1729. doi: 10.2215/CJN.15590920. Epub 2021 Apr 5. PMID: 33820759; PMCID: PMC8729407.
What is the differential diagnosis?
The slides showed :
a.H&E stain: IF/TA
b.Arterial multilayering
C.PAS stain: tubular wrinkling and thicking of basement membrane with interstitial infiltrate around atrophic tubules.
-This feature suggested chronic allograft dysfunction.
Causes of chronic allograft dysfunction:
1.chronic rejection.
2.. CNI toxicity
3. BK nephropathy
4.DM ,hypertension ,CV diseases
5. urinary tract infection or obstruction.
What is your management plan?
-Explain the situation to the patient, with appropriate psychosocial support.
-Bk virus screening and DSA.
-DM and hypertension control
-Avoid nephrotoxins.
-Maintain good fluid balance.
-CNI reduction: target level 4-8ng/ml.
-early discussion regarding future dialysis, and possible retransplantation.
-Creation of dialysis access.
Very clear plan and management, Excellent
The biopsy showed tubular atrophy with interstitial fibrosis and intimal arterial thickening
DD
Chronic allograft nephropathy
AMR
CNI nephrotoxicity
Management plan
-decrease tacrolimus dose
-manage comorbidities
-monitor DSA, proteinuria , serum creatinine
-screen for infection
-c4 d staining
– explain to the patient the possibility of dialysis ,or Rerenal transplantation
Reference
Li X, Zhuang S. Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation. Fibrogenesis Tissue Repair. 2014;7:15.
Excellent
Histology shows ;
A. H&E stain; interstitial inflammation and fibrosis, tubular atrophy, no glom or vessel seen
B. PAS stain; a vessel was seen with evidence of arteriolar hyalinosis, and fibrinoid necrosis(anion skin appearance)
C.C4d stain in peritubular capillaries = capillaritis
Differential diagnosis ;
other causes of Chronic allograft dysfunction; CNI, BK nephropathy, recurrence or de novo disease, HTN, DM, pyelonephritis, donor-derived
Management; Unfortunately the evidence for treatment of chronic AMR is not robust.
a. Keep immuno-suppression optimal. The Tac level of 9 may be high at this point post-transplant. 5 to 6 may be optimal
b. Review compliance
c. Control of HTN, DM, and dyslipidemia
d. Check DSA level
e.CKDT pathways management; anaemia, PTH, Ca, P
f. Preparation for another transplant, or HD including the plan for access creation
Mixed rejection ?! What is there to suspect that.
Otherwise acceptable plan.
Figure 1 Tubular atrophy can be recognized in this figure by the presence of tubules showing greater than 50% reduction in diameter compared to surrounding non-atrophic tubules. Atrophic change affects more than half of the sampled parenchyma (ct3).
Figure 2 Kidney transplant IF/TA with concentric duplication of the intima of a large artery (periodic acid–Schiff stain).
Figure 3Tubular atrophy in a usual pattern with thickened, wrinkled tubular basement membranes with simplified tubular epithelial cells and contraction of the tubular lumen adjacent to intact tubules
What is the deferential diagnosis?
Chronic CNI toxicity
Chronic antibody-mediated rejection
Transplant glomerulopathy
Chronic pyelonephritis or reflux nephropathy
Viral infection
What is your management plan?
1-DSA level
2-reduce the dose of CNI
3- Screening for the virus by the PCR
4- Control of blood pressure, blood glucose.
5-Treatment of infection according to the result of infectious screen
6-Think of access for dialysis
References
1. Coll E, Crespo M, Solé M. Lessons from cyclosporine monotherapy in renal transplantation: The impact of acute rejection on long-term allograft outcome. Transplant Proc. 2004;36:S114–S116. , et al. (Suppl): [PubMed] [Google Scholar]
Excellent
Histology explanation : The images given correspond to interstitial fibrosis and tubular atrophy. Tubular atrophy corresponds to the presence of tubules with thick redundant basement membranes, or a reduction of greater than 50% in tubular diameter compared to the surrounding non-atrophic tubules.
Interstitial fibrosis is considered when the supporting connective tissue in the renal parenchyma exceeds 5% of the cortical area.
Differential diagnosis
Management
References
What about the middle slide. Blood vessel.
IFTA with concentric duplication of intima of large artery. Using periodic acid Schiff stain (PAS).
This is IF/TA which can be caused by:
1- chronic allograft injury
2- transplant glomerulopathy
3-BK nephropathy
4- CNI toxicity
Plan of management:
1-DSA level
2-reduce TAC dose
3-look for anti C4d staining in the biopsy
4-BK virus PCR in serum
In the first slide, many tubuli seem atrophic there is hypercellularity and this means a chronic event in addition to rejection which may happen at any time. late rejections are mostly AMBR, so we need c4d staining.
in the third picture here is vacuolation in some tubular and atrophy with marked BM thickening,n trophies ones also hypercellularity is present as in the first slide
second I think this is a thick walled artery (hyalinosis?)
It is logical to keep the patient on lower immunosuppression decreasing the target tough level of TAC and consider a second transplant evaluation. If no donor is available, close monitoring and evaluation for AVF will be discussed with the patient.
☆What is the deferential diagnosis?
____________________________________
These slides shows intestinal fibrosis, tubular atophy and intimal fibrosis of blood vessels
◇Differential diagnosis:
1. Chronic renal allograft dysfunction [1] that result from AMR [2]
2.Chronic nephrotoxic effects of calcineurin inhibitors [3]
3. hyperfiltration injury, and dyslipidemias [4]
3. Viral infection.
◇What is your management plan?
__________________________________
1. Serial determinations of serum creatinine and proteinuria
3. DSA level
4. C4d staining
5. Viral screening
6.Therapeutic drug monitoring (with a narrow therapeutic window of Tacrolimus level).
▪︎NOTE: The use of sirolimus or MMF in place of CNI may lead to a temporary improvement in GFR, however, there are no randomized, controlled trials supporting a long-term benefit from this strategy [4].
7. Hypertension and hyperlipidemia should be rigorously controlled if present, the former preferably with either an ACEI or ARB [4].
8. Control of DM if present
9. Treatment of infection according to the result of viral screening
10. Inform the patient about the high risk of allograft rejection and the need of dialysis.
____________________________
Ref:
[1]Musab S. Hommos and Andrew D. Rul “Should we always defer treatment of kidney disease when there is extensive interstitial fibrosis on biopsy?
https://dx.doi.org/10.1159/000449513
[2] Xiaojun Li and Shougang Zhuang “Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation”
https://dx.doi.org/10.1186/1755-1536-7-15
[3] Egeland E.J., et al. A. High tacrolimus clearance—A risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: A retrospective single-center cohort study. Transpl. Int. 2019;32:257–269. doi: 10.1111/tri.13356.
[4] Brian J. Nankivell. “Chronic Allograft Nephropathy “. Kidney Transplantation (Sixth Edition), 2008
GFR is 17 ? Sirolimus will not be suitable
Thanks prof Dawlat
DD
1- chronic AMR
2-chronic CNI toxicity
3- chronic infection pyelonephritis, BK virus
there is IF/TA, arterial thickening and c4d deposition
management:
1- strict control of bl.p and blood glucose
2-diet control to delay dialysis
3-prepare for soon dialysis …check access
4-DSA screening for future retransplantation
5-decrease dose of tacrolimus to avoid more toxicity
6- close follow up clinically and laboratory
Very well remark of antibodies screening for future Tx not nesesarily DSA.
Thank you.
Will you shift him to sirolimus while his eGFR is 17ml/min?
mTORi not indicated if ;
GFR>40
First slide shows IFTA ( H&E stain) , second slide shows a section of large blood vessel with intimal fibrosis & concentric re-duplication of intimate( PAS stain), third slide Showa atrophic tubules with wrinkled & this basement membrane.
Differential diagnosis:
Management plan:
Prevalence of C4d positivity was different between studies. Most studies show statistical association of C4d positivity & chronic transplant glomerulopathy. Prevalence of pre transplant anti HLA class II in chronic TG ~ 75-80%, but prevalence of C4d positivity only 24-36%.
References:
Excellent Ban, totally agree with you.
Thank you sir
Keeping in mind that this is a 17 yr old graft with GFR of 17 ml and chronic changes on biopsy is suggestive of chronic allograft Nephropathy.
The possibility of chronic rejection cannot be ruled out.
I think we need to keep a lower Tac level
He requires optimum CKD management and consideration for future transplant
Excellent, yes and also think of access for dialysis
What is the differential diagnosis?
The slides above show:
Micrograph 1: IFTA
Micrograph 2: thickened arteriolar wall and arteriolar hyalinosis
Micrograph 3: positive C4d staining, multilayering of cappilary walls, proximal tubular cells vacuolization, peritubular capillary cellular infiltration.
DIFFERENTIAL DIAGNOSIS:
chronic allograft rejection- chronic changes and positive C4d- needs screening for DSA
chronic tacrolimus toxicity- tacrolimus level is higher than the target
BK virus nephropathy
What is your management plan?
Excellent, yes and also think of access for dialysis
Slide A show interstitial fibrosis with tubular atrophy (IFTA).HE stain
Slide B show thickening of Arterial wall. HE stain
Slide C show tubular atrophy and tubular wrinkling and interstitial fibrosis -by PAS stain
Renal fibrosis is a histological hallmark of CKD and CAN and believed to be a pathogenic intermediate for progression to failure.
DDX
ABMR
TCMR
Medical events (DM,HT))
CNI toxicity
BK nephropathy
Recurrence of diseases
Treatment
An earlier index of suspicion of chronic allograft nephropathy with periodical blood work and clinic visits
Screening for DSA, BK
Check for non-adherence with IS
early biopsy for diagnosis
intensive control of blood pressure,glucose and cholesterol levels and proteinurea
CNI reduction or CNI withdrawal may be the ideal early interventional strategy for the prevention and treatment of CAN.
Reference
Chronic Allograft Nephropathy By Professor Ahmed Shoker Professor of Nephrology and Transplantation University of Saskatchewan CANADA
The term CAN is replaced now by Chronic allograft dysfunction
Thank you
The first slide demonstrates interstitial fibrosis, a condition in which tubules are not lined up behind one another (stain is H&E stain) tubular atrophy with focal lymphcyte infiltration.
The subintimal thickening of the arterial wall throughout all of the layers is seen in the middle slide.
The third slide, stained with PAS shows peritubular capillary multilayers. and there is infiltration of the capillary with lymphocytes(chronic rejection).
this is going with chronic allograft injury for DD:
IFTA of unknown aetiology
chronic antibody-mediated rejection(need DSA positive or C4D staining to confirm the diagnosis)
transplant glomerulopathy(need glomerulus to check the double contour of capillary basement membrane).
BK Nephropathy( need PCR and SV40 stain).
chronic T-cell mediated rejection.
recurrence of original kidney disease.
non-immune mediated conditions include CNI toxicity, blockage or reflux illness, return of the underlying native condition, and secondary reasons such as diabetes or HTN.
conservative: 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. targeting lower tacrolimus levels 4-5.
If the C4D is positive or DSA +VE, I will deal with the patient as a chronic AMR.
treating with pulse steroid plus IVIG /or rituximab with CMV and PCP prophylaxis could be an option.
What do you mean by IF/TA of unknown etiology?
Any explanation
It means no clear cause for the interstitial fibrosis and tubular atrophy(immunological and non-immunological, like CNI within normal limit, no chronic disease, no signs of rejection, no obstructions, and no recurrent UTI.
Dear Weam
“The third slide, stained with PAS shows peritubular capillary multilayers. and there is infiltration of the capillary with lymphocytes(chronic rejection)”.
I disagree with you. It shows tubular atrophy and thickened tubular basement membrane
Chronic allograft injury including iIFTA in the first slide of LM with H&E stain, with dense interstitial inflammation and fibrosis, marked arteriolar fibrous intimal thickening in the middle slide and the third slide is sliver stain which is the best stain used to see the tubular GM thickening( thick BM in black) with ischemic injury wrinkling and area of tubular atrophy with some ATN with cytoplasmic vocalization and interstitial inflammation .No IHC staining given in these slides to assess for C4D staining.
This graft from DD with standard immunological risk two mismatches , induction with basiliximab and on adequate maintenance IS since 17 years with clinical and histological evidence of chronic damage which could be multifactorial including immunological and nonimmunological causes likes Chronic rejection including previous TCMR and chronic Active ABMR rejection we don’t have glomerulus to assess for chronic transplant glomerulopathy also EM important to assess for GBM multilayering ,Chronic Active AMBR ?, chronic transplant glomerulopathy however I would expected some proteinuria with such lower GFR so the non-immunological causes of chronic damage including uncontrolled hypertension ,diabetes, dyslipidemia cardiovascular and peripheral vascular diseases , viral infection in particular BKN ,CMV nephropathy , chronic CNI toxicity especially in the presence of high tacrolimus trough level in the presence of some histological acute isometric ATN ( any recent drug-drug interactions ) is he on regular ACEI or recent use of ACEI or recent use of IVIG ( for rejection or viral infection ?) ,recent contrast exposure or any drug with osmotic effect that can explain the focal area of ATN with isometric cytoplasmic vocalizations on back ground of chronic injury including recent use SGLT1 ? nil proteinuria supporting the diagnosis of chronic CNI toxicity with in the given trough level which is high for the period of transplant especially he is on tacrolimus based and MMF (target tacrolimus should be 5-7ng) another DDX BKV nephropathy So, to complete the picture we need to know the base line GFR for the last 3-6 months, BP control, tacrolimus trough level, comorbid like CVD, DM, uncontrolled BP
Previous history of TCMR or AMR
DSA levels, C4D -staining
BKV and CMV status need to do SV40 Staining for BKV and BKV PCR level, EM for double counter and GMB multilayering
Mean while will need to control BP , remove any nephrotoxic medications reduce tacrolimus dose and further options of treatment will be directed accordingly
Reference:
1- prof Ahmed shakor lecture chronic allograft nephropathy .
Very impressed Saja
The biopsy revealed IFTA, with tubular atrophy, renal tubular vacuolization ,diffuse mononuclear cells infiltration and arterioalar medial hypertrophy
Differential diagnosis:
Chronic allograft nephropathy
1]Chronic rejection .
2]CNI related IFTA
3]BKV nephropathy.
4]CMV nephropathy
5] Covid 19 Nephropathy.
6]Hypertensive nephropathy.
management:
1}minimizing CNI
2} Exclude CMV and BKV infection bu PCR test.
3} Its basically stage 4 CKD,for assessment of CKD complications and management thereof, may be creation of vascular access to prepare for HD.
4} I would advise for enrollement on KAS.
Very impressed Wael
What did you mean by KAS?
Please explain the abbreviations
What is the deferential diagnosis?
Slide A:
L/M: showing interstitial fibrosis with tubular atrophy. (IFTA).
Slide B:
L/M: showing multi-layering wall of blood vessels.(changes of chronicity which may be due to recurrent rejection or part of medical co-morbidity like HTN/drug induced CNI).
Slide C:
C4d staining in PTC showing positive and wrinkling of peritubular wall (chronic changes).
Indicative to check DSA to complete criteria for diagnosis CAMR.
What is your management plan?
This was a deceased donor kidney transplantation with excellent graft survival more than 17 years with high tacrolimus level showing mainly CAN due to immunological and non-immunological causes so,
1-decreasing CNI dose or trying to withdrawal CNI.
2-Serial f/u of associated medical condition (blood glucose , blood pressure , uric acid and lipids profile) and with strict control of these conditions.
3-Check DSA and BK viruses.
4-Treatment of associated co-morbidity of CKD status like (hyperparathyroidism and anemia if present).
5-Close f/u of the recipient discussing with him other modalities of RRT.
Thank you
Slide C is a Periodic Acid Schiff (PAS) stain that stains the basement membrane showing thickened basement membrane and atrophic tubules, also, there is interstitial cellular infiltration around the atrophic tubules. Please follow the question about C4d staining posted by Prof Dawlat Belal
Dear All
It will be very useful to add the benefit of listening to this week’s lecture to diagnose this case.
Also for decision taking for management read the paper in the journal club about treatment in similar cases.
LM:
shows IF/TA.
There is vacuolation .
Double of GBM(in silver stain).
DD:
CNI toxicity.
CABMR.
Transplant glomerulopathy
Chronic CNI toxicity:
Can occur with different Trough level ,even normal wont exclude 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.
Duplication of GBM.
·
Monitoring of CNI trough level. reduce the dosage.
Third slide shows C4D staining of PTC. Rather than GMB.
This goes with CABMR.
still CNI toxicity should be considered ,dose adjusted
Control of Blood pressure.
In patient with CABMR treatment is difficult ,a combination of corticosteroid and
IVIG is suggested.
Reference:
Arjng Djamali et alKidney transplantation in adults: Prevention and
treatment of antibody-mediated rejection of the renaallograft.Uptodate.Feb 28, 2020.
Good it will be useful to attend the lecture of this week about chronic allograft nephropathy
Also journal club (treatment of chronic allograft nephropathy.
In the current scenario of old renal transplant with history of 1 DR mismatch and induced as standard immunologic risk with Basiliximab which gives good idea about suitability of pretransplant PRA and cross matching. Presented with low GFR and no proteinuria as well as high Tacrolimus level which supposed to be at the level of 4-7 ng/ml.
First slide from the left showing interstitial fibrosis where in tubules are not back to back (stain is H&E stain ,the preferred stain to demonstrated fibrosis is Trichrome stain)
Middle slide showing Arterial wall thickening across all the layers.
Third slide from the right with PAS stain (mainly used for demonstration of basement membranes) showing tubular atrophy and interstitial fibrosis (I am not sure for presence C4d staining in view of absence of IF or IHC staining?)
What is the deferential diagnosis?
DD will be for chronic allograft dysfunction which can be immunologic and non immunologic:
1-Immunologic like chronic active ABMR (needs proper biopsy to assess glomeruli for chronic AMR ,chronic active TCMR).
2-Non immunologic causes:
-Chronic CNI nephrotoxicity
-Recurrence of and de novo glomerulonephritis
-BK associated nephropathy
-late or recurrent acute rejection
-renal artery stenosis
What is your management plan?
*Honestly the images provided indicate Chronic allograft Nephropathy (CAN) which replaced now with interstitial fibrosis and tubular atrophy (IF/TA), without evidence of any specific etiology.
So to diagnose the current situation we need:
1-Enough graft biopsy sample including 8-10 glomeruli with at least 2 arteries to be examined with light microscopy ,IF and electron microscopy.
2-Check DSA level
3-CNI minimization or withdrawal if there is evidence of CNI toxicity
4-Check BKV PCR level
-Finely it is a failing transplant with extensive IFTA for optimization of immunosuppression and control of BP.
Very good comment of the value of glomeruli to examine the basement membrane even with HE
IF if C4d is suspected and further study of BM if needed
Your conclusion and management plan is very good.
What if C4d is positive any comment?
Also tubular BM can show the multilayered effect on EM
Thank you Dr.Dawlat,
If C4d is positive with other histological picture of chronic active ABMR will manage differently with optimization of immunosuppression and monitoring of DSA level in addition to other conservative measures as control of BP.
if C4d is positive in the context of IFTA, its indicative of chronic active AMR.
I would investigate the DSAs by solid phase method , particularly Luminax plate in order to classify it and explore its density, keeping in mind he is a potential kidney recepient of a second transplant.
Thank you, Dr Mohamed.
Slide C is a Periodic Acid Shiff (PAS) stain that stains the basement membrane showing thickened basement membrane and atrophic tubules, also, there is interstitial cellular infiltration around the atrophic tubules.
What is the differential diagnosis?
Renal biopsy shows Interstitial fibrosis & tubular atrophy (i-IFTA) and isometric tubular vacuolization in FIGURE -1 , Arterial wall thickening & hyalinosisin figure -2, and Positive C4d staining in PTCs in figure -3.
Differential Diagnosis: chronic CNI toxicity leading to chronic allograft injury, Chronic rejection and BK nephropathy.
What is your management plan?
Modification of immunosuppressive regimen ( decrease the dose of CNI (keep the tacrolimus level between 5-7 ng/ml i.e., towards the lower target (5 ng/ml)or CNI-free regimen )
Control of other factors if present like HTN, DM, hyperuricemia, and hypercholesterolemia
If on ACE inhibitors or ARBS we have to shift to alternative antihypertensive which is safe in lower GFR and proteinuria
Check for BK virus and DSA level
Prepare the patient for RRT(dialysis OR re-transplant)
Last comment is very logic and informative to the patient.
Description and analysis is fine
But if positive C4d with this advanced chronicity what would be your plan.
Thank you
Slide C is a Periodic Acid Schiff (PAS) stain that stains the basement membrane showing thickened basement membrane and atrophic tubules, also, there is interstitial cellular infiltration around the atrophic tubules. Please follow the question about C4d staining posted by Prof Dawlat Belal
What is the differential diagnosis?
What is your management plan?
Very good what about the third slide any comment in view of the rest of the findings.
C4d staining of PTC may suggest chronic ABMR, but no specific treatment could be added to the previous plan due to advanced chronic kidney disease
What is the deferential diagnosis?
Figure 1(left):
– Interstitial fibrosis & tubular atrophy (i-IFTA)
– Interstitial inflammation, edema, & tubulitis
Figure 2(middle):
– Arterial wall thickening & hyalinosis
Figure 3(right):
– Positive C4d staining in PTCs
Differentials
– Chronic active ABMR
– Chronic allograft nephropathy
– Hypertensive arterosclerosis
What is your management plan?
– Optimal blood pressure control
– Optimize CNI dose
– Consider CNI minmization or withdrawal
– Check DSA
– Check for BK virus
– Prepare for RRT (dialysis, re-transplant)
Reference
The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials
Excellent
Slide C is a Periodic Acid Schiff (PAS) stain that stains the basement membrane showing thickened basement membrane and atrophic tubules, also, there is interstitial cellular infiltration around the atrophic tubules.
1st slide: striped fibrosis
2nd slide: arterial hyalinosis
3rd slide: isometric tubular vacuolization
Features of chronic CNI toxicity leading to chronic allograft injury.
Other DDx:
Reference:
Kidney transplantation principles and practice textbook 8th edition by Stuart J Knechtle, Loran P Marson, Sir Peter J Morris.
This is more likely.
The first slide on the right is C4d staining
Middle slide as you correctly mentioned is arterial wall thickening and hyalinosis.
The slide on the left shows interstitial fibrosis and tubular atrophy.
No glomerulus is seen to comment on the basement membrane to diagnose TG.
So add DSA and virus screen for BK
Thank you
slide 1 shows IFTA and interstitial inflammation
slide 2 shows intimal fibrosis, hyalinosis and thickening of basement membrane
slide 3 shows C4d positivity
D/D
chronic rejection / mixed
CNI toxicity
BK virus
increase dose of tacrolimus to achieve a level ~12
pulse steroids followed by oral dose 1mg/kg followed by taper
IvIg