3. A 57-year-old man received kidney transplant 15 years ago. Over the last 3 years, his serum Cr kept rising gradually. Initially was 131 µmol/L now 193 µmol/L. His is on triple immunosuppression (cyclosporine based). No proteinuria. USS showed well-perfused kidney, RI 0.7. Transplant kidney biopsy below:
- What else you need to know?
- Describe the histological finding?
- What is your differential diagnosis?
Dear All
Thank you for your replies. 3 questions
1-chronic CNI toxicity which is called striped pattern fibrosis or band like.
2-TMA recurrence can appear any time in post transplant course but mainly in the first 3 months after TX especially with activating factors like IR injury, drugs or associated diseases like APLs or atypical HUS).
3-I think no need with current situation especially if no past history of previous attack before and chronicity pattern without systematic manifestation.
The pattern of CNI toxicity here is a chronic CNI with stripped fibrosis.
-There is a chronic hemodynamic changes causes afferent arteriolar hyalinosis,ischemia and fibrinoid necrosis.
-It is important to check for complement activation to rule out chronic active or chronic ABMR which is the main differential diagnosis in this scenario.
1.Striped pattern interstitial fibrosis & tubular atrophy.
2.Associated ifections e.g CMV,BK etc
Possibility of a ccompanying late ABMR (endothelial injury)
High trough level of CNI.
Changing from one CNI to anothe may also be responsible,though unlikely in this case as it is not mentioned in the scenario.
3.YES
Precipitating factors for TMA include:
i. Phenotypical shift of C3 glomerulopathy (?cause of ESRD in the Patient) to aHUS
post transplantation
ii. Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent
TMA) ???? that late recurrence
1. Please describe the pattern of CNI toxicity seen on the slide on the right side
Striped pattern fibrosis, seen with CNI toxicity.
2. You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
This seems to be de-novo TMA, which can be due to CNI.
3. Is it important to check for complement activation in this case?
Yes. Although the clinical scenario points towards CNI toxicity,the underlying antibody mediated rejection needs to be evaluated
1- chronic CNI toxicity characterised by focal IFTA in striped pattern with arteriloar hyalnosis sometimes its very diffcult to differentiate from the chronic active cellular rejection in the area of dense infammation and both can coexistes and put the patinet at risk of AMR on longterm
2-late conversion from CNI based IS with introduction of everolimus or sirolimus which could be the case we need more history espcailly there is no protienuria .
3- yes to differentiate between complement mediated TMA from secondary TMA
The pattern of CNI toxicity is stripped fibrosis.
TMA in such case could be due to CNI. I doubt that at this stage he merits any further work up like complement activation.
I think if this was due to some gene mutation leading to complement activation this would have occurred much earlier
good reasoning
Is there a possibility of TG in the biopsy if yes what is with
If no what is against.
Yes there is possibility
TG might evolve from smoldering TMA of various causes
There is a possibility of TG (chronic allograft nephropathy) that is characterized by the presence of interstitial fibrosis and tubular atrophy as well thus mimics the CHRONIC CNI toxicity.
●●What is with :
1- PATCH FIBROSIS & TUBULAR ATROPHY.
2- VASCULAR AFFECTION in the form of intimal thickening and narrowing of the vascular lumen. These changes are similar to those seen in the thrombotic microangiopathies.
3- Glomerulosclerosis.
●●What is against :
1-The TG present witb double contour glomerular membrane (that is not seen in CNi toxicity) where
the glomerular capillary walls are thickened with an occasional double-contour appearance, resembling that seen in membranoproliferative glomerulonephritis (MPGN) but without dense deposits.
2- Chronic immune rejection was uncommon with prolonged follow-up, i.e the TG occurs more within the 1st year post tx while later it is attributed more to the I.supp. ttt ( e.g CNI).
3- Other causes than CAN, the principle causes of chronic kidney allograft dysfunction include:
☆Chronic antibody-mediated rejection (ABMR)
☆Diabetic kidney disease (recurrent
or de novo)
☆Recurrent or de novo
glomerulonephritis,
☆BK polyomavirus associated nephropathy,
☆ Late acute rejection
☆Renal artery stenosis.
●☆●
CAN must primarily be distinguished histologically from those disorders that can cause a predominant interstitial fibrosis and/or a membranoproliferative glomerulonephritis (MPGN) pattern on kidney biopsy:
●Disorders also making Interstitial fibrosis : The presence of marked interstitial fibrosis due to CAN must be differentiated from other causes of fibrosis, particularly the typical “striped fibrosis” induced by calcineurin inhibitors (CNIs; eg, cyclosporine or tacrolimus).
In this setting, histologic evidence of the characteristic glomerulopathy or the presence of peritubular capillary basement membrane splitting and lamination is most consistent with CAN.
By comparison, the detection of newly formed hyaline arteriolar changes is specific for cyclosporine nephrotoxicity.
●Disorders also Membranoproliferative glomerulonephritis – The MPGN pattern of transplant glomerulopathy (TG) must be distinguished from other glomerular disorders, particularly MPGN that is associated with hepatitis C virus (HCV) infection or is due to recurrent or de novo disease. These disorders may appear similar on light microscopy.
The distinction is made on electron microscopy, which typically shows thickening and duplication of the glomerular basement membranes without immune deposits in TG; by comparison, there are prominent subendothelial immune deposits in HCV-associated MPGN.
1-Its striped fibrosis.
2-TMA can be a recurrent ,drug or infectious and malignancy induced.
3- yea ,if Suspect AHUS.
What is the possibility of reccurent aHUS after 15 years comment on
Time of reccurence
survival of the graft in 15 years
Systemic manifestations.
Recurrent is less common than denovo and more earlier if lead to ESrD in
short time.
More risk to graft survival .
Can be with systemic manifestation(anemia,thrombocytopenia..) or
localized to renal with renal failure.
1. Please describe the pattern of CNI toxicity seen on the slide on the right side
Chronic calcineurin inhibitor nephrotoxicity is manifested at all levels of nephron compartments including glomerulus, arterioloes, tubules and interstitium.
At vascular level chronic CNI toxicity causes obliterative arteriolopathy and ischemic collapse or scarring of the glomeruli. At the level of tubules, CNI causes vacuolization of the proximal tubules, while glomeruli are affected in terms of global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial striped fibrosis.
2. You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
TMA in the late post-transplant period is rare but when occur it is associated with increased risk of graft loss. CNI toxicity is among the differential but still ABMR should be considered in the differential and also viral illnesses.
3. Is it important to check for complement activation in this case?
Yes. The acute presentation should raise the possibilities of CNI toxicity, ABMR, viral illnesses like parvovirus, CMV, and EBV. Malignancy should aldo be excluded as the patient is on immunosuppressed.
blood pressure
cyclosporine trough level
C4d staining
CMV PCR
right side: stripped interstitial fibrosis
left side: TMA
CNI nephrotoxicity can occur any time after start of therapy
TMA
infection as CMV
chronic CNI toxicity in the form of patchy fibrosis
TMA can be caused by reccurence of 1ry kidney disease like TTP and HUS but this will occurs early post transplant
TMA 15 years post transplant it can be caused by acute CNI toxicity related to adding drug with enzymatic inhibitor to cytochrome p450 causing CNI toxicity
or ABMR .
yes ,systemic disease will be associted with low complemnt
kidney localized disease will be associated with normal complement
1-Please describe the pattern of CNI toxicity seen on the slide on the right side .
Stripped fibrosis ( tubular atrophy with interstitial fibrosis).
2- You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis. TMA after transplantation can be classified into either: (1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant; and (2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation. Since renal biopsy of native kidney is not performed in many patients with end stage renal disease (ESRD), missed diagnosis of TMA prior to kidney transplantation is likely. With the advent of the drug eculizumab, an anti C5 monoclonal antibody, that is highly effective
in prevention as well as treatment of atypical hemolytic uremic syndrome (aHUS), it would be crucial to know the etiology of ESRD in order to differentiate de novo from recurrence.
3- Is it important to check for complement activation in this case?
Yes,
Chua et al[41] reported that renal complement activation is the common denominator in such a heterogeneous condition. They observed C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA from a heterogenous group of patients[41]. Moreover, Le Quintrec et al[7] reported the presence of genetic mutations in CFH, Complement Factor I(CFI) or both in 29% of their studied de novo TMA patients, 25% showed low Complement Factor B (CFB) and/or low C3, suggesting an AP complement activation. No mutations have been found in healthy controls (100) or in TMA-free KTR controls[7].
References:
1. Reynolds JC, Agodoa LY, Yuan CM, Abbott KC. Thrombotic microangiopathy after renal transplantation in the United States. Am J Kidney Dis. 2003;42:1058–1068.
2. Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (Orlando) 2018;32:58–68.
41. Chua JS, Baelde HJ, Zandbergen M, Wilhelmus S, van Es LA, de Fijter JW, Bruijn JA, Bajema IM, Cohen D. Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy. J Am Soc Nephrol. 2015;26:2239–2247.
1- pattern is : stripped fibrosis of chronic
CNI toxicity which is focal areas if tubular
atrophy & interstitial fibrosis.
This pattern could be seen in high as
well as low doses of CNI.
There is possibly as well, an arteriolar
hyalinosiS which is the hallmark of any
CNI nephrotoxicity, THAT IS
IRREVERSIBLE IF occured within 3 ys of
high or even low doses of CNI.
CNI TOXICITY COULD BE POSSIBLY
LOWERED by ( ANTI TGF beta ) therapy.
2- Could be denovo TMA ( usually takes
days to weeks) or
secondary to infection( CMV, Parvo v., BK)
, drugs or diseases like Apls or atypical
HUS while in other situations could be
2ry to ischemic reperfusion injury( IR).
3- Complement check is important to investigate for :
Complement mediated TMA
Atypical HUS
Chronic ABMR
Sorry i meant the denovo TMA occurs within 3 to 6 months if it was due to CNi toxicity as far as i read
(link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134269/)
While the recurrent TMA could occur days to weeks after the transplant.
Striped **
1) its striped interstitial fibrosis
2) most probably de novo TMA, may be related to CNI toxicity as evidence by other HP slide,
3) i think yes, complement activation should be checked to r/o Atypical HUS also, although it also appear early in post Tx period
There is striped tubulointerstial fibrosis with monocytic cells infiltration.
TMA could be a manifestation of AMR, but no clear signs are demostrated in biopsy, except for glomerular capillary thrombosis.
Complement activity assay has to be performed to detect aHUS that can happened at any time, however no past history was reported. Complement mediated TMA can be secondary to infection or malignacy, which has to be investigated and excluded on a solid base, given the long term history of immunosupression.
–interstitial fibrosis (strip fibrosis) and tubular atrophy .
-recurrence usually with in first year (3 month)but may reoccur after years less common
-we think now with denovo TMA so need to exclude infection ,drug ,malignancy .
important to send for complement activation in this case .
1-Pattern of CNI toxicity -stripped interstitial fibrosis
2-Infections like CMV, BK virus, high trough level of CNI or associated ABMR
3-Yes to rule out chronic AMR
Pattern of CNI toxicity
Causes of post transplant TMA
Evaluation of complement
Reference
1.CNI levels (now and previous), DSA monitoring, C4d staining, BK and CMV PCR, SV40 staining
2.left: TMA right: striped fibrosis indicative for CNI toxicity
3.CNI toxicity, Chronic ABMR, recurrence of aHUS or TTP
what else you need to know
trough level of cyclosporine
blood pressure assessment
C4d
Histological finding :
stripped interstitial fibrosis
DD
CNI toxicity
Chronic rejection
TMA
CNI toxicity pattern consist of focal fibrosis or stripped interstitial fibrosis and tubular atrophy without inflammation , glomerular collapse to sclerosis
TMA may related to CNI toxicity
complement activation should be checked for the possibility of antibody mediated rejection
1) What else you need to know?
Explore history of potential nephrotoxic medications. Compliant to immunosuppressant. Any history of infection especially COVID 19. Any high risk behavior.
Serial blood pressure and diabetic control and check for evidence of CSA toxicity.
2) Describe the histological finding?
Stripped interstitial fibrosis. Thicken basement membrane with intravascular thrombus.
3) What is your differential diagnosis?
CNI Toxicity.
Antibody mediated rejection.
Uncontrol hypertension/ Diabetes mellitus.
TMA
CMV/ BK viraemia.
4) Please describe the pattern of CNI toxicity seen on the slide on the right side.
Stripped interstitial fibrosis with lymphocytic cells infiltration at the interstitium.
5) You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
CNI toxicity
Malignancy.
CMV/ BK Varaemia.
6) Is it important to check for complement activation in this case?
Yes to rule out possible of antibody mediated rejection.
chronic CNI allogtraft toxicity, mostly of the stripped fibrosis pattern
indeed, TMA is commonly occur in the eralt post transplantation days, however, this seems de novo TMA type mostly secondary to CNI chronic toxicity.
Yes, to rule out AMR.
History: any history suggestive of infection, malignancy, or NSAID use
Investigation: CBC, CRP, U/E/C, urine R/E and proteinuria, CsA trough level
DSA, C4d staining, EM examination
1st on left:
double contour GBM, microthrombi in glomerular capillary, with hyalynosis?
2nd right
inflammatory cell infiltration with fibrosis ( Stripped fibrosis) and area of normal looking tubules.
1- CNI toxicity
2- Chronic ABMR
3- TMA
4- interstitial glomerulonephritis
5- BK infection
6- TG
Other tests required
Histology
Image 1
Image 2
Differential diagnosis
What else do you need to know?
1. Compliance with immunosuppressant medications (including trough level of CNI).
2. Native kidney disease.
3. DSA level.
Describe histological findings?
The left image shows a section containing about 4 glomeruli examined by light microscopy.
The right image shows one glomerulus examined by light microscopy showing:
Thickened basement membrane.
Thrombi within the glomerular capillary.
Homogenous pink material near 6 O’clock.
What is the differential diagnosis?
1. TMA.
2. FSGS.
3. AMR.
History wise:
Native kidney disease lead to renal failure, compliance on medications and follow up checks especially Cyclosporine level, any change of dosage, and other drug history which might interact with IS, history of previous sensitization or rejection episode, Blood pressure control history, any symptoms suggestive of hemolysis, malignancy (fevers, loss of weight, GIT, Respiratory) and finally urinary symptoms.
Examination wise: signs suggestive of malignancy, hemolysis, rashes, Fundus.
Laboratory wise: FBC, blood film, haemolytic panel (LFT, Haptoglobin, blood film, LDH, reticulocytes count), CNI trough levels, C3, C4, C4d, ch50, urine RM, and culture. Virology screen (Hepatitis, CMV, BK, parvovirus, EBV)
Imaging wise: USS and doppler were OK.
Left Picture: one glomerulus, thick basement membrane, intra-glomerular capillary thrombi.
Right Picture: interstitial fibrosis, tubular atrophy, stripped pattern fibrosis, the picture is clear enough to judge about arterial hyalinosis
Both are suggestive of CNI toxicity
1- CNI toxicity (Cyclosporine in this clinical scenario)
2- Chronic ABMR
3- TMA Causes: Recurrent (HUS, TTP, malignant HTN, auto-immune) vs De-novo which might include (ABMR, CNI associated, m-TOR inhibitor associated, viral infection, PTLD malignancy, missed before TX, genetic abnormality in complement pathways)
In this case, it looks like cyclosporine induced TMA which is usually non-immune TMA and is dose related secondary to high levels of CNI or prolonged exposure with high cumulative dose.
Q1- What is the cyclosporin level
Q2- Stripped fibrosis and tubular atrophy
Q3- acute or chronic antibody mediated rejection
Cyclosporin toxicity
Transplant glomerulopathy.
TMA can occur de novo triggered by immunosuppressive drugs.
Yes impotant to check for complement activation
1-What else you need to know?
I want to know
1. Underlying cause of renal failure .
2. Mismatch and DSA status before transplant.
3. History of any rejection
4. History of drug adherence and previous cyclosporine drug level.
5. Family history of any renal failure A HUS ?
6. Blood pressure and history of proteinurea .
2- Describe the histological finding?
RT slide shows strip fibrosis with tubular atrophy – a feature of chronic CNI toxicity .
LT slide shows fibrin microthrombi suggesting thrombotic microaangiopathy .
3-What is your differential diagnosis.
· CNI toxicity .
· ABMR
· TG
· THROMBOTIC MICROANGIOPATHY
o Drug induced (CNI, sirolimus )
o Recurrence of AHUS ( although it is occur early post transplant period )or denovo HUS .
o ABMR
o Infection ( CMV ,HIV ..)
Malignancy
I want to know
CNI level with level history .
DSA before and after transplantation
original kidney disease
viral infections like CMV, BK virus infection, EBV
CNI dose and patient adherence to medications .
Shows thickening of basement membrane with stripped fibrosis
CNI toxicity , Chronic Antibody Mediated Rejection, viral infection
We need to know compliance to medications,, cyclosporine trough levels, DSA, CMV PCR quantitative
Histological finding
Interstitial fibrosis of stripped pattern with tubular atrophy suggesting CNI toxicity
Differential diagnosis
CNI toxicity ,chronic AMR and TMA.
Complement evaluation will help to explore for complement mediated TMA ,AHUS and chronic ABMR
Q1: What else you need to know?
Q2:Describe the histological finding?
Q3: What is your differential diagnosis?
Thanks
Q1: What else you need to know?
Q2:Describe the histological finding?
Q3: What is your differential diagnosis?
1. Full history regarding blood pressure control , nephrotoxic drugs , UTI
DSA , Cyclosporine trough level and CMV PCR
2 . Stripped pattern IFTA suggesting Tx Glomerulopathy
3. DD : CNI Toxicity
Chronic AMR
TMA
There is fibrosis which is mostly due to CNI toxicity. we need to know the drug level and staining for cd4 to rule out chronic rejection that led to fibrosis
dd: CNI toxicity, chronic TMA as seen on left photo (?)
1.DSA level,c4d staining
Cyclosporine level
C3 level
Hypertension whether adequately controlled
Hcv pcr
primary disease of kidney
2.first showing transplant glomerulopathy or chronic tma and second showing stripped fibrosis.
3.Acute cni toxicity in background of chronic
abmr or recurrent glomerular disease.
1.what else you need to know :
CsA level, original disease, DSA
2. image 1: TMA – hemorrhage in glomerular tuft
Image 2: stripped interstitial fibrosis
3. Differential Diagnosis :
CNI toxicity, late antibody mediated rejection, TG
WHAT ELSE YOU NEED TO KNOW?
PRIMARY KIDNEY DISEASE PLUS ANY SYSTEMIC DISEASE AS HUS LUPUS .
DSA PRE AND AFTER TRANSX.
MEASURED LEVEL OF CYCLOSPORIN AND WHY KEPT FOR LONG PERIOD.
FAMILY HISTORY OF ANY IMMUNOLOGICAL DISEASES
viral infections like CMV, BK virus infection, EBV
Describe the histological finding?
SHOWS THICKNING OF BASMENT MEMBRANE WITH STRIPPED FIBROSIS.
DIFFERTIAL DIAGNOSIS?
CNI TOXICITY, CH ABMR, TUBULOGLOMERULOPATHY
AS AREPLY TO DR AHMED HALAWA
describe the pattern of CNI toxicity seen on the slide on the right side
CHRONIC CNI TOXICITY AS SEEN PATHCES OF FIBROSIS IN THE GLOMRULI .
What caused TMA which is usually an acute event in the early post-transplant period to happen?
COULD BE ARESULT OF CNI TOXICITY AS PER HISTORY PATIENT TOOK IT FOR LAST 15 YEARS PLUS APOSSBLITY ABMR.
Is it important to check for complement activation in this case?
SURE AS IF IT IS ASYSTEMIC DISEASE IT WILL HAVE COMPLEMENT DEPLTION IF NORMAL IT POINTS TO ALOCALIZED RENAL PROBLEM.
What else you need to know?
-primary glomerular disease lead to renal failure .
-immunohistochemistry or immunofluorescence to exclude any Ab mediated rejection EX (PTCc4d).
-adherence to drug .
Describe the histological finding?
histological finding with TMA ,with chronic interstitial fibrosis
(strip fibrosis) and tubular atrophy.
What is your differential diagnosis?
the most common cause for intrgraft TMA is (Ab mediated rejection )and should be first to put in differential diagnosis regardless early or late presentation .
-acquired cause for TMA, virus CMV, BK .
-CNI related that need to change to MTOR .
Q1) unfortunately Im still not keen on histologyy
Q2) TMA might occur in CNI toxicity , in the context of ABMR
Q3) Yes in order to exclude ABMR
Regarding the history: asking about diabetes and blood sugars , control of blood pressure, compliance for medications, NSAIDS , diarrhea , fever , dysuria , original kidney disease.
Assessment of the volemic status
Labs: complete blood count, cyclosporine trough level and peak level, MMF level, urine analysis, urine C&S, DSA, C4D on the biopsy, CMV PCR quantitative .
* Left :
Basement membrane double contour, suggesting transplant glomerulopathy
Right :
Interstitial fibrosis
Tubular atrophy
*Differential diagnosis:
Calcineurin inhibitor toxicity
Chronic antibody mediated rejection
1. What else you need to know?
2. Describe the histological finding?
3. What is your differential diagnosis?
It is necessary to know:
– patient’s history of hypertension;
– cyclosporine dosages (any recent elevation?)
– history and evaluation of infections (hepatitis, HIV)
Draws attention focal areas of interstitial fibrosis indicating chronic allograft nephropathy
The fact that there is no proteinuria and the time for disease progression point against transplant glomerulopathy. It does not rule out the chronic rejection phase. And glomerulopathy due to the use of cyclosporine, hypertension, infections are part of the differential diagnosis.
I need to know cyclosporine level & complement activation system
Striped fibrosis
1)CNI toxicity
2)Denovo TMA(infection, malignancy)
1) its striped interstitial fibrosis
2) most probably de novo TMA, may be related to CNI toxicity as evidence by other HP slide,
3) i think yes, complement activation should be checked to r/o Atypical HUS also, although it also appear early in post Tx period
cyclosporine trough level
blood pressure
DSA
C4d staining
CMV PCR
left side: TMA involving the glomerular tuft and the vascular pole (Jone silver stain)
right side: stripped interstitial fibrosis (Jone silver stain)
CNI nephrotoxicity can occur any time after start of therapy
TMA related to antibody mediated rejection should be excluded, the patient had DSA, biopsy shows significant microcirculation inflammation (peritubular capillaritis or glomerulitis) and peritubular capillary C4d deposition
TMA related to malignant hypertension
infection as CMV
Lusco MA, Fogo AB, Najafian B, Alpers CE. AJKD atlas of renal pathology: calcineurin inhibitor nephrotoxicity. American Journal of Kidney Diseases. 2017 May 1;69(5):e21-2.
Ávila A, Gavela E and Sancho A (2021) Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front. Med. 8:642864.
1-I need to know the drug level
2-TMA +STRIPPING IFTA both attributed to CINI toxicity
3- DD AMR that why we will do C4d stain
Diarrhea can cause CNI toxicity by increasing the Transient absorption time in the GI tract
What else you need to know?
– Trough level of cyclosporine.
– primary kidney diseases .
– history of previous rejection .
– DSA , C4d staining .
– serology ( HCV infection ).
– history of drugs e.g : NSAID .
– history of hypertension.
Describe the histological finding?
RT : glomerulus with silver stain with fibrin thrombi due to TMA due to ABMR , thickening glomerular basement membrane (transplant glomerulopathy ).
LT : tubules stained with PAS stain showed stripped fibrosis ( tubular atrophy with interstitial fibrosis ) .
What is your differential diagnosis?
-chronic ABMR .
– Cyclosporine toxicity.
– Recurrence of primary disease.
– other causes of TMA e.g : malignant HTN or aHUS.
What else you need to know?
I will like to know- Cause of ESRD, cPRA, DSA pre transplant . RI is normal and no proteinuria, CNI levels are required
Describe the histological finding?
Interstitial Fibrosis stripped pattern
What is your differential diagnosis?
Chronic CNI Toxicity
Chronic AMR
Thrombotic microangiopathy
Please describe the pattern of CNI toxicity seen on the slide on the right side?
stripped fibrosis
You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
Poor adherence to medication
BK infection
Is it important to check for complement activation in this case?
Yes ,DSA or positive c4d would point to AMR rather than CNI toxicity
What else you need to know?
patient compliance to medications, cyclosporine level , any history of AMR,
Describe the histological finding?
The glomerular membrane is thick and at 7,8 and 11 O’clock, glomerular fibrin deposit, stripped fibrosis and tubular atrophy
What is your differential diagnosis?
TMA due to CNI toxicity or chronic active AMR
What else you need to know?
I will like to know- Cause of ESRD, cPRA, DSA pre transplant . RI is normal and no proteinuria, CNI levels are required
Describe the histological finding?
Interstitial Fibrosis stripped pattern
What is your differential diagnosis?
Chronic CNI Toxicity
Chronic AMR
Thrombotic microangiopathy
– Live or deceased donor
– Cross match with the donor and if any DSA
– Types of Is medications and if any change in the regimen or in the dose
– If CNI based regimen , what is the level
– Any history suggesting infection
Right picture:
Interstitial fibrosis- stripped pattern
Tubular atrophy
left picture:
Basement membrane double contour, suggesting transplant glomerulopathy
fibrin microthrombi
What is your differential diagnosis?
1) chronic CNI toxicity
2) Chronic antibody mediated rejection
3) Thrombotic microangiopathy: de novo likely, due to either CNI or chronic AMR.
Question for all. How would you manage this condition now? What is your target FK506 level? Any roles of CNI sparing agents?
Shift to tacrolimus maintaining target of 5-7 ng/ml if there is C4d staining or DSA or target of 3-5 ng/ml if no clinical features of chronic ABMR
Late conversion to sirolimus > 6 months was found to be associated with increase in the rate of BPAR and no improvement of CAN, so I did not recommend conversion.
Convert cyclosporine to tacrolimus.
Target level less than 3.5ng/ml is likely to invite rejection
CNI minimization using MMF or sirolimus may modestly increase in CrCl) & decrease SCr in the short term
Bear in mind that MTORIs, like CNIs, is also linked to TMA.
Change to Tacrolimus with keeping minilam normal teough level 3_4 ng/ml. optimizing the dose of MMF and prenisolon.
mTori might be anther plan especially if DSA is low.
Striped tubulointerstitial nephritis due to CNI toxicity. In consistance with this suggestion is the normal resistive index and no proteinuria.
Trough Cyclosporin level is needed as well as EM study to visialize the vaculation of renal tubular cells. Similarly Immunoflouricent study is indicated to exclude C4d positive chronic rejection and BK nephropathy
Differential diagnosis is chronic rejection and BK nephropathy
good plan
Could this be an acute CNI toxicity with drug induced TMA
Or chronic effect after 15 years.
What factor in the clinical scenario is against chronic active ABMR
What is with?
Its chronic CNI toxicity and not acute., clinical picture and biopsy showed striped Chronic interstitial nephritis in consistance with CNI.
Absence of proteinuria is against chronic active AMR.
There are two lesions, one is striped interstitial nephritis of chronic CNI toxicity, and TMA which is relatively an acute onset event. I would like to know if there is any evidence of systemic TMA. There is no clear histological finding of AMR.
Striped tubulointerstitial nephritis due to CNI toxicity. In consistance with this suggestion is the normal resistive index and no proteinuria.
Trough Cyclosporin level is needed to confirm the diagnosis.
Differential diagnosis is chronic rejection.
The slide of renal biopsy shows stipe interstitial fibrosis which could be caused by CNI toxicity.
Post transplant TMA can occur at any time but commonly occur early in first 3 months. PS TMA can be caused by:
1. Recurrence of TMA ( eg aHUS)
2. De novo PT TMA due to type of donor ( more in DBD & DCD), drugs ( CNI, mTOR-I), ABMR, infection, malignancy , pregnancy or missed diagnosis before transplant.
No need for complement activation checking because at time of transplantation the complement cascade already activated which may be due to type of donor and ischemia perfusion injury or even due to ABMR.
Thankyou for mentioning the TYPE OF DONOR for TMA but then this should have been very early on.
What about other pathology findings seen in the glomerulus.
The left slide shows one glomerulus with multiple endocapillary fibrin thrombi
What else you need to know?
Describe the histological finding?
Typically striped interstitial fibrosis .
CNI Toxicity:
Acute CNI Toxicity:
Functional toxicity (ACUTE Arteriolopathy.):
· Mild decrease in renal function and increase in serum creatinine, hypertension in
50%, reversible if dosage lowered and no morphologic changes in kidney
· Toxicity due to alteration in intrarenal hemodynamics (vasoconstrictive
phenomenon).
Acute tubular toxicity:
· Similar to functional toxicity but more severe microscopic changes include
vacuoles in proximal tubules (due to dilated endoplasmic reticulum with giant
mitochondria, large lysosomes) and microcalcifications.
· Also arteriolar smooth muscle cell degeneration, endothelial cell swelling, intimal
thickening, variable hyaline or mucoid deposits which narrow lumen
· Dose dependent and reversible
Thrombotic microangiopathy:
· Resembles hemolytic uremic syndrome
· Occurs days to weeks after transplantation
· Glomeruli and vessels show thrombotic microangiopathy with platelet and fibrin
thrombi and minimal inflammatory infiltrate
Chronic toxicity:
· Hypertension and slow progression to renal failure.
· Arterioles show nodular or diffuse hyalinosis of vessel walls or mucoid
thickening of intima, leading to luminal narrowing.
· Also diffuse interstitial fibrosis and tubular atrophy.
· Early glomerular changes are aggregates of platelets and fibrin
· Late changes are focal and segmental glomerulosclerosis or global scarring
· Changes are irreversible
What is your differential diagnosis?
CN toxicity.
AMR
CAN.
BK infection.
T. glomerulopathy.
References:
Naim Issa Aleksandra Kukla Hassan N. Ibrahim .Calcineurin Inhibitor Nephrotoxicity: A
Review and Perspective of the Evidence tension, University of Minnesota, Minneapolis,
Minn. , USA.Am J Nephrol 2013;37:602–612 DOI: 10.1159/000351648 .
Thankyou for generous review of information
If you are asked to downsize your choices to help to diagnose which ones would be reasonable?
In your final differential diagnosis:
Is it TG orABMR
CAN is replaced by chronic allograft nephropathy
BK INFECTION is a good option.
GOOD EFFORT BUT NEEDS TO BE MORE SPECIFIC KEEP TRYING.
History: Regarding the control of blood pressure, any non-adherence of medications, intake of any other medications, any infections.
Lab tests: complete blood count, cyclosporine trough levels, DSA, CMV PCR quantitative
Left Panel:
Basement membrane double contour, suggesting transplant glomerulopathy
fibrin microthrombi
Right Panel:
Interstitial fibrosis- stripped pattern
Tubular atrophy
1) Calcineurin inhibitor toxicity
2) Chronic antibody mediated rejection
3) Thrombotic microangiopathy: de novo likely, due to either CNI or chronic AMR.
Higher chances of due to CNI as no proteinuria
Infection like CMV is also unlikely as no history provided.
Welldone.
What else you need to know?
Describe the histological finding?
What is your differential diagnosis?
Good choice of further investigation but:
ADAM3 could be dropped as recuurent aHUS is unlikely after 15 years with this level of graft function and no history or systemic manifestations.
Malignant hypertension is acceptable option.
Renal artery stenosis??
I would like to know DSA and complement levels, cyclosporine levels, history of diabetes and hypertension, hbA1c, subsequent blood pressure recordings, PCR CMV, urinalysis, blood culture, stool culture, C4d staining.
The slide shows striped interstitial fibrosis – a feature of CNI toxicity.
The morphological lesions may be absent in functional CNI induced vasoconstriction leading to reduced kidney function. Thrombotic microangiopathy, isomeric tubular vacuolization, nodular hyalinosis, extending to the media of arterioles and arteries.
Differential diagnosis :
REFERENCES:
Thankyou Nandita for the information BUT:
to reach a clinical decision try to stick to the information given in the scenario
as no hypertension or diabetes were mentioned
Whatis confirmed is
interstitial lesion suggestive of chronic cyclosporine toxicity
15 years post tx. with glomerular pathology of TMA for this try to find a cause by the further tests you asked for.
No proteinuria.
KEEP TRYING.
1- Other required data include ;
A- primary kidney disease.
B- Other extrarenal manifestations specially heamatological as hemolytic anemia and thrombocytopenia to DD limited from systemic form of TMA
C- B. P
D- Viaral status specially CMV , BK virus
E- CNI trough level.
F- Assess AMR with DSA and C4d stining of graft biopsy.
2- 1st picture show intraglomerular fibrin thrombi , 2 nd image show sripped pattern of interstitial fibrosis.
3- DD
TMA that may be either
a- De no vo TMA related to
· Malignant HPN
· Drug SE specially CNI, m TOR
· AMR
· Genetic mutation in complement pathway
b- Recurrent TMA
What are the features that favor chronic ABMR over CNI toxicity?
Transplant glomerulopathy, peritubular capillary inflammation, & C4d deposition are more specific for chronic ABMR.
This is generally speaking, but I am not if all these are seen or done in this case(e.g no mention for IHC or IF staining)
Features favoring chronic ABMR in this case include:
Transplant glomerulopathy: Basement membrane multilayering.
In a patient with chronic ABMR, as per Banff criteria, there should be morphologic evidence of chronic tissue injury, presence of DSA and peritubular capillary C4d positive staining or moderate intravascular inflammation.
Such patients usually have proteinuria
CNI nephrotoxicity feature ,such as striped interstitial fibrosis, arteriolar hyalinosis,
tubular atrophy, and glomerulosclerosis.
Double contouring of GBM and IF ,tubular atrophy more with CAN.
In our case rt slide (double of GBM) but generally inflammatory cells in Peritubular capillary with C4d positive(IF/IHC) with multilayering of blood vessels especially in E/M.
DSA positive.
Transplant glomerulopathy – glomerular capillary walls are duplicated diffusely, capillary lumen is narrowed, and swelling of endothelial cells seen, some inflammatory cells. Peritubular capillaritis, thrombotic microangiopathy, C4d positive.
Reference:
Katsuma, A., Yamakawa, T., Nakada, Y. et al. Histopathological findings in transplanted kidneys. Ren Replace Ther 3, 6 (2017). https://doi.org/10.1186/s41100-016-0089-0
clinically , protienuria
histology , LM combination chronic tissue injury , IFTA with chronic vascular inflammation ,with multilyayring of the PTCbasement membrane chronic artiolopathy with fiberous intimal atrophy EM will shows the widening and the typical multilayring of the BM ,IF shows the C4D staining in PTCS
C4d staining and detection of DSA
Chronic antibody-mediated rejection
1- presence of C4d staining in the peritubular capillaries
2-Positive testing for donor-specific antibodies (DSAs)
3-transplant glomerulopathy
4-proteinurea
ABMR is best described in thecontext of Banff criteria ; tissue injury, evidence of antibody interactions with endothelium, & the presence of DSA. recently is the use of molelular classifier & gene expression profiles.
What else you need to know?
Describe the histological finding?
Interstitial fibrosis
What is your differential diagnosis?
Good begining Filipe but always ask yoursle
f what is the significance of every item asked for for example
Viral panel good choice
DSA good choice
CNI level very justified
complement level? what acute complement activating process are you suspecting.
your final d.d diagnosis is fine but what histological findings in the given slide indicate TCMR. try to revise that.
good start keep trying.
Thank you, Professor Belal. I need to study more histological findings. I did not do the first Module, so I believe to get better.
Please describe the pattern of CNI toxicity seen on the slide on the right side
You noticed that the transplant happened 15 years ago. What caused TMA which is usually an acute event in the early post-transplant period to happen?
TMA that occur late after many years of transplantation may be due to :
So immunosuppressive drugs may be incriminated in this patient either due to direct toxicity (drug induced TMA) or due to over suppression leading to infections or malignancy related TMA
Is it important to check for complement activation in this case?
REFERANCES
1. Lahlou A, Lang P, Charpentier B, et al. Hemolytic uremic syndrome. Recurrence after renal transplantation. Groupe Coopératif de l’Ile-de-France (GCIF). Medicine (Baltimore) 2000; 79:90.
2. Al-Nouri ZL, Reese JA, Terrell DR, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015; 125:616.
Exellent and organised as usual Sherif your reasoning to reach the conclusion is v good.
Thanks alot Dr Dawlat
I advice newcommers to read Sherif’s answer as an example.
Thanks a lot Professor Belal for guidance
What else do you need to know?
-Take a careful history of diarrhea, an orginal disease that causes ESRD, and examine for petechiae and purpura.
-BP and examine fundi.
-DSA, C4d, and cyclosporine level.
-Urinalysis, Blood and stool cultures,
-CBC (Hb, platelets) and blood film for RBC fragmentation.
-LFT, LDH.
– Viral screening HCV, CMV, BK, and parvovirus.
-Immunological screening (ANA,dsDNA) ,complements.
-ADAMTS13 activity.
Describe the histological finding?
-Thrombi in the glomerular capillaries, double contouring of glomerular capillaries
and thickening of GBM in the right slide
-There cellular infiltrate and stripped fibrosis and atrophy of tubules in the left slide
What is your differential diagnosis?
-TMA is a histological diagnosis that results in thrombosis in capillaries and arterioles, due to an endothelial injury. Post-transplant TMA may occur de novo, or recurrence TMA.
De novo TMA can be due to :
1. Antibody-mediated rejection.
2. Immunosuppressive-associated TMA: CNI or mTOR inhibitors.
3. Viral infection: e.g., HCV, CMV, BK, and parvovirus.
4. Genetic abnormalities in the complement cascade.
5. Missed diagnosis of TMA in the native kidney as a cause of ESRD.
Recurrent TMA after renal transplantation can be due to :
1 -Hemolytic uraemic syndrome or Thrombotic thrombocytopenic purpura.
2. Malignant hypertension.
3. Autoimmune disorders like SLE.
Fedaey Abbas, Mohsen El Kossi, Jon Jin Kim, Ajay Sharma, and Ahmed Halawa. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant. 2018 Sep 10; 8(5): 122–141.
Thankyou all for your responses .To reach a diagnosis you have to adopt some analytical reasoning for the clinical and lab information:
1 Stripped interstitial fibrosis is clear ly obvious.
question:is a trough cyclo level always high or is it the 15 years duration?
2.Is it TMA
If it is it is a DE NOVO why?
reccurent aTMA occurs very early with a + history and systemic manifestations,and the graft would not have survived that long.
DE NOVO TMA
You all asked correctly to exclude the causes which can occur at any time during the 15 years
Two differential diagnosis need discussion:
a. Is it chronic active ABMR? double contour of BM, fibrin thrombi ,C4d can be positive or negative, you also asked for DSAs a picture very suggestive of TG??
BUT it was clearly mentioned there is NO PROTEINURIA despite the impaired kidney functions which weakens this option as a solid diagnosis.So canTG coexist with chronic cyclo. toxicity.?
* What else you need to know?
* History of patient recent exposure to viral infection / Current Medication to rule out drug interaction/ Adherence to his immunosuppressive agents/ last drug level/ history of hypertension / CBC peripheral blood film for presence of schizocytes /LDH / Urine R/E, drug level of cyclosporine / serial level of DSA .
* case of gradual loss of graft may due to cyclosporine toxicity and complement activation may risk to Thrombotic microangiopathic thrombosis. Anti mediated rejection associated thrombotic microangiopathy may risk to graft loss when DSA bind to HLA loci on surface of endothelium lead to activation of complement (C3,C4), so biopsy is diagnostic and can treated with aggressive immunosuppressive agents like Belatacept and stop cyclosporine and switch to another type like tacrolimus.
* Describe the histological finding?
* first picture: biopsy of one glomeruli shows evidence of intracapillary thrombi & thickening of basement membrane.
* second picture interstitial fibrosis & tubular atrophy
* What is your differential diagnosis?
* case of chronic allograft rejection may be 1. transplant glomerulopathy 2. cyclosporine induced nephropathy
* anti phospholipids syndrome
* 3. TTP / HUS
* Ana Ávila, Eva Gavela, and Asunción Sancho; Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity: Front Med (Lausanne). 2021; 8: 642864.
* Published online 2021 Apr 8. doi: 10.3389/fmed.2021.642864
*