Renal transplant vasculitis

Mostafa Sharifian MD
Professor of Pediatric
Nephrology
Shahid Beheshti University of Medical Sciences, Tehran
Renal transplantation in
children with vasculitis

Renal transplantation in children with vasculitis
My talk will cover:
- Causes of ESRF Leading to transplantation(Tx)
- Overview of Tx in children with or without Vasculitis
- Vasculitis types Leading to Tx
- Treatment approaches in the world
- Prognosis of Tx in Vasculitis
- Our experience in Tx in children with vasculitis

Kidney transplantation is considered the
treatment of choice for children with ESRD
because it is associated with:
Better quality of life,
Productivity and regular school attendance,
Growth and cognitive development of children,
Longer patient survival than what can be achieved
by other modalities (PD, HD)

Understanding the primary renal diseases is
essential prior to kidney transplantation.
A number of primary renal diseases can recur in
transplanted kidney, but this is not a contraindication
to transplantation.
Recurrent disease accounts for Graft loss in almost:
7% of primary transplantations and
10% of repeat transplants.

Common Causes of ESRD in Pediatric Transplant Recipients (N: 11186)
CAUSES % OF RECIPIENTS
Aplasia, hypoplasia, dysplasia 15.8
Obstructive uropathy 15.3
Focal segmental glomerulosclerosis 11.7
Reflux nephropathy 5.1
Chronic glomerulonephritis 3.1
Polycystic disease 3.0
Medullary cystic disease 2.7
Congenital nephrotic syndrome 2.6
Hemolytic-uremic syndrome 2.6
Prune belly syndrome 2.5
Familial nephritis 2.2
Cystinosis 2.0
Crescentic glomerulonephritis 1.7
MPGN type I 1.7
Pyelonephritis/interstitial nephritis 1.7
SLE nephritis 1.5
Renal infarct 1.3
From: North American Pediatric Renal Trials and Collaborative Studies 2014

Recurrence rate after KTx
Disease % Recurrence % Graft loss
Primary FSGS 30–60% #25%
primary hyperoxaluria 100% 30%
MPGN type 1 20–70% #30%
MPGN type 2 # 100% #50%
IgA nephropathy # 50%
HSP 30%
Wilms tumor 13%
Anti GBM <5% 50%

All patients with ESRF are candidate
for kidney transplantation
unless contraindicated

In
Past
Protocols:

Now not a
barrier for
Tx

Renal transplantation is a therapeutic option in AAV patients.
There are several publications clearly indicating that AAV patients do
fairly well after renal transplantation and that AAV should definitely not
be considered as a contra-indication for transplantation ,
However, there are several issues regarding the treatment of
AAV before and after transplantation that remain unresolved
Epidemiology of AAV and transplantation,
Timing of transplantation,
Risk of relapse,
Role of ANCA measurements and
Treatment of relapses after transplantation.

Timing of transplantation
An exacerbation of vasculitis, the induction therapy given to curb it, the
transplantation operation as well as the anti-rejection therapy all inflict stress on
the immune system increasing the risk for opportunistic infections.
It seems logical to postpone transplantation until the patient is in remission and
the immune system has recovered from the induction therapy.
This seems to be the common practice in Europe, according to a survey presented
by Little et al :
In the study evidence was found that patients transplanted <12 months after
diagnosis of AAV had increased mortality and tended to exhibit vasculopathy on
transplant biopsies.
Other studies have failed to see any relationship between time since last flare or
after onset of dialysis therapy and adverse outcome.
Actually even some patients transplanted with ongoing disease activity have been
reported to do well.

Immunoglobulin A vasculitis (IgAV), formerly called Henoch-Schönlein purpura (HSP)
HSP Is the most common systemic vasculitis of childhood.
90% of cases occur in the pediatric age group.
In contrast to other forms of systemic vasculitis, IgAV (HSP) is usually self-limited and is
characterized by a tetrad of clinical manifestations that vary in their presence and order
of presentation:
●Palpable purpura in patients with No thrombocytopenia nor coagulopathy
●Arthralgia and/or arthritis
●Abdominal pain
●Renal disease

Long-term Outcome of Renal Transplantation Patients with Henoch-
Schönlein Purpura, Based on: UNOS database
Samuel JP,* et al, Clin J Am Soc Nephrol. 2011 Aug; 6(8):2034–2040.
Background and objectives: Although Henoch-Schönlein purpura (HSP) is the most common form of renal vasculitis in
childhood, progression to ESRD is rare, and there are few data on outcomes of renal transplantation in patients with HSP.
Design, setting, participants, & measurements
This is a matched retrospective cohort study of renal allografts using the United Network of Organ Sharing database
(1987 to 2005). Of the 189,211primary renal allografts, there were 339 with a diagnosis of HSP.
The primary end point was allograft survival.
Results: Compared with the remainder of the database, the HSP population was younger (25 years versus 46 years), and had a higher proportion of women
(47% versus 40%), live donors (50% versus 35%), and Caucasians (77% versus 60%). Controlling for age, gender, donor source, ethnicity, and year of
transplantation, death-censored graft survival for patients with HSP was 80.0% at 5 years and 58.8% at 10 years compared with 79.0% at 5 years and 55.4%
at 10 years in the non-HSP population. Among patients with reported causes of graft loss, failure from recurrent disease occurred in 13.6% of patients with
HSP, compared with 6.6% in the non-HSP population. When analyzing allograft survival in recipients with HSP compared with those with IgA nephropathy,
there was no difference in 10-year allograft survival (58.4% and 59.3%)
Conclusions: These data indicate that although there is an increased risk of graft failure attributable to recurrent disease in patients with HSP, a diagnosis
of HSP has little effect on overall renal allograft survival.

Kaplan–Meier estimates of death-censored allograft survival in patients with Henoch-Schönlein purpura
(HSP) and matched controls (log-rank test, P = 0.57)

Kaplan–Meier estimates of death-censored allograft survival in patients with (HSP) and matched controls,
separated by donor source (log-rank test, deceased donors, P = 0.45; and living donors, P = 0.98).

Kaplan–Meier estimates of death-censored allograft survival in patients with Henoch-Schönlein purpura (HSP)
and graft loss, comparing those with graft loss caused by recurrence versus other causes (log-rank test, P = 0.29)

Complication HSP Group (n = 103; 100%) Matched Group (n = 271; 100%)
Chronic allograft
nephropathy
52 (50.5) 137 (50.5)
Hyperacute/acute rejection 18 (17.5) 51 (18.8)
Recurrent diseasea 14 (13.6) 18 (6.6)
Other 6 (5.8) 10 (3.7)
Noncompliance 4 (3.9) 12 (4.4)
Infection 4 (3.9) 8 (3.0)
Primary nonfunction 2 (1.9) 13 (4.8)
Graft thrombosis 2 (1.9) 14 (5.2)
Surgical/urological
complication
1 (1.0) 8 (3.0)
aFisher exact test comparing failure caused by recurrence versus any other cause (P = 0.04).
Allograft failure in the matched groups (UNOS)

Long-term Outcome of Renal Transplantation Patients with Henoch-Schönlein Purpura
Joyce P. Samuel,* Cynthia S. Bell,* Donald A. Molony,† and Michael C. Braun , Clin J Am Soc Nephrol. 2011 Aug; 6(8): 2034–2040.
Background and objectives
Although Henoch-Schönlein purpura (HSP) is the most common form of renal vasculitis in childhood, progression to ESRD is rare, and
there are few data on outcomes of renal transplantation in patients with HSP.
Design, setting, participants, & measurements
This is a matched retrospective cohort study of renal allografts using the United Network of Organ Sharing database (1987 to 2005).
Of the 189,211 primary renal allografts, there were 339 with a diagnosis of HSP. The primary end point was allograft survival.
Results: Compared with the remainder of the database, the HSP population was younger (25 years versus 46 years), and had a higher
proportion of women (47% versus 40%), live donors (50% versus 35%), and Caucasians (77% versus 60%). Controlling for age, gender,
donor source, ethnicity, and year of transplantation, death-censored graft survival for patients with HSP was 80.0% at 5 years and
58.8% at 10 years compared with 79.0% at 5 years and 55.4% at 10 years in the non-HSP population. Among patients with reported
causes of graft loss, failure from recurrent disease occurred in 13.6% of patients with HSP, compared with 6.6% in the non-HSP
population. When analyzing allograft survival in recipients with HSP compared with those with IgA nephropathy, there was no
difference in 10-year allograft survival (58.4% and 59.3%, respectively).
Conclusions: These data indicate that although there is an increased risk
of graft failure attributable to recurrent disease in patients with HSP, a
diagnosis of HSP has little effect on overall renal allograft survival.
Renal transplantation in children with vasculitis- UNOS

Renal Transplantation in Antineutrophil
Cytoplasmic Antibody-Associated Vasculitis:
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a
common cause of rapidly progressive glomerulonephritis resulting in ESRD.
The optimal timing of kidney transplantation (KTX) for ESRD as a result of AAV
and the risk of AAV relapse after KTX are not well defined.
A Multicenter Experience by Geetha D. et al
Transplantation. 2011 Jun 27; 91(12): 1370–1375.
Background
We report our experience with AAV patients who underwent KTX at our institutions between
1996 and 2010. Median follow-up was 64 months.

Renal Transplantation in ANCA-Associated Vasculitis:
A Multicenter Experience by Greetha D. et al, Transplantation. 2011 Jun 27; 91(12): 1370–1375.

Results
85 patients (45 men/40 women; mean age 49 years) received a KTX for ESRD secondary to
microscopic polyangiitis (n=43) or Wegener’s granulomatosis (n=42).
24 patients underwent preemptive KTX and 69 received a living-donor KTX.
All patients were in remission at the time of KTX. Fifty-eight patients received induction
therapy. In 64 patients, maintenance immunosuppression was with prednisone, mycophenolate mofetil,
and tacrolimus. At the time of KTX, 29 patients were ANCA-positive. The vasculitis relapse rate was 0.02
per patient-years and was not influenced by disease category, ANCA subtype, or remission duration
before KTX. There were 23 rejection episodes in 13 patients with seven graft losses. Median serum
creatinine at 1 year was 1.3 mg/dL in 75 patients with more than 1 year follow-up and 1.4 mg/dL at last
follow-up. Graft and patient survival were 100% at 1 year, 97.9% and 93.4% at 5 years, and 79.0% and
67.4% at 10 years
Conclusion: KTX is a safe and an effective option for treating ESRD secondary to AAV.
Relapses are rare with current immunosuppression.
Transplantation in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
(AAV): A Multicenter Experience,
Duvuru Geetha, et al. Transplantation. 2011 Jun 27; 91(12): 1370–1375.

We conclude that transplantation should be considered as the treatment of choice for ESRD due to AAV.
Potent antirejection regimes are well tolerated in these patients, are associated with a low risk of
recurrence and absence of AAV-related graft dysfunction.

Renal
transplantation
in children with
vasculitis

Renal transplantation in children with vasculitis- French study
French study

Renal transplantation in children with vasculitis- French study
A total of 66 patients with a diagnosis of AAV during childhood between 1986
and 2011 have been included (28 GPA, 23 MPA and 15 renal-limited AAV).
MPA and renal-limited AAV had similar features and were grouped together
for this study (n = 38).
The average annual incidence of reported cases over the 25-year period was
0.22 (95% CI 0.04, 0.62) per million children, increasing from 0.10 in 1986–90
to 0.45 per million children in 2006–10.
Median age at diagnosis was 11.5 years (IQR 9.6–13.1). There was a
predominance of girls (75% in GPA and 89% in MPA) The median follow-up
time was 5.2 years.
During follow-up, 22 patients (34%) reached ESRD and 15 additional ones (23%)
developed chronic kidney disease. ESRD occurred in 7 out of 28 (25%) patients
with GPA and in 15 out of 38 (39%) patients with MPA.
Among ESRD patients, 17 were transplanted and 5 were on dialysis at last follow-
up. Renal survival was 74 (CI: 65–87), 70 (CI: 60–83) and 59% (CI: 45–77) at 1
year, 5 years and 10 years after diagnosis, respectively

Long‐term outcome of renal transplantation in childhood‐onset anti‐neutrophil cytoplasmic
antibody–associated vasculitis, Takeshi Nagasawa, et al, 16 January 2020
Background:
There have been a few reports of RTx for AAV in children; however, post‐transplant recurrence
rate and long‐term prognosis remain unclear. Here, we describe the long‐term outcomes of RTx
in childhood‐onset AAV.
Methods: We conducted a retrospective study of children who underwent RTx for AAV
between 1999 and 2017 and had a follow‐up period of >2 years.
Results: Seven patients consisting of three children with MPA and four with RLV were analyzed.
Age at Dx was 5.9 (median; range, 4.1‐14.5) years. PD was instituted in all patients, and median
time on dialysis was 26 (range, 14‐63) months. Age at RTx was 12.8 (median; range, 8.7‐16.3)
years. There were no recurrences of AAV noted during the median follow‐up period of 7.0
(range, 2.7‐18.8) years after RTx. Graft loss occurred in one patient due to non‐adherence.
Estimated glomerular filtration rate of the remaining patients at the last follow‐up was 73.0
(median; range, 50.7‐93.9) mL/min/1.73 m2. No malignancies and deaths occurred during the
observational period.
Conclusions: Our study suggests that RTx for AAV with ESRD is a potentially safe and effective
treatment choice for children with AAV.

Actuarial survival rate, estimated by Kaplan-Meier method in patients with and without recurrent disease (P<0.0001).
Abbreviations: RD, recurrent disease.
38
RECURRENT AND DE NOVO
GLOMERULAR DISEASE AFTER
RENAL TRANSPLANTATION: A
Report from Renal Allograft
Disease Registry (RADR)1,2
Hariharan, Sundaram; Adams,
Mark B.; Brennan, Daniel C.;
Davis, Connie L.; First, M. Roy;
Johnson, Christopher P.; Ouseph,
Rosemary; Peddi, V. Ram; Pelz,
Corey J.; Roza, Allan M.; Vincenti,
Flavio; George, Varghese
Transplantation68(5):635-641,
September 15th, 1999.
doi:

CASE REPORT: Crescentic IgA nephropathy along with simultaneous cellular and
antibody‐mediated rejection in a kidney transplant leading to rapid allograft failur
Clinical Case Reports, Volume 7, Issue 9

Light microscopy: Fibro-cellular crescent formation and mesangial proliferation

Light microscopy: Sclerosed glomeruli with interstitial inflammation and tubular atrophy.

Glomerular Crescent. The capillaries also show mononuclear cells indicative of glomerulitis.

gA immunofluorescence showing mesangial deposition of IgA.

Immunofluorescent stained sections showed focal mesangial and capillary wall deposits for IgA.

The role of ANCA testing
Despite its limitations ANCA is a commonly used biomarker for disease activity in AAV.
It has been shown that persistent ANCA-positivity during remission is a risk factor for relapse.
Consequently it would not be surprising if ANCA-positivity at the time of transplantation would be a risk
factor for later relapses. This is, however, not a uniform finding in published reports.
In a pooled analysis we did not find any statistically significant relationship between ANCA-positivity at
transplantation and subsequent relapses.
Elmedhem et al reported on eight patients, 4 being positive and 4 negative at transplantation, two relapses
were recorded both in patients being ANCA- negative at transplantation.
On the other hand Geetha et al. found ANCA at time of transplantation to be a risk factor for relapse.
In many patients with flares, a rise in ANCA is a late event, so if ANCA is less helpful for prediction it can still
help to distinguish relapses from other causes of renal impairment.
Patients who are ANCA-positive at time of diagnosis will in most cases also be positive at time of relapse and
ANCA levels will be increased.
The ability of ANCA-tests to confirm a flare does not seem to be blunted after transplantation, positive tests
at time of relapse was noted in 3/3, 5/5, 2/2 and 7/7. cases.
Renal transplantation in ANCA-associated vasculitis, Mårten Segelmark, Sweden
2013, La Médicale, (42), 4, 568-571.

Treatment of relapses
Treatments recorded in case series include most therapies used for AAV
patients who have not been transplanted, such as:
Corticosteroids alone,
Increased basal immunosuppression,
Cyclophosphamide,
Rituximab and various combinations of these agents.
Recurrent disease in the grafts seems to respond well to
cyclophosphamide in most reported cases.
In the RAVE trial, Rituximab exhibited superior to induce complete
remission in relapsing patients as compared to cyclophosphamide.
As disease activity after transplantation always is relapse, rituximab is
from a theoretical standpoint an attractive alternative.
2013, La Médicale, (42), 4, 568-571.

Conclusion: Renal transplantation should be the treatment of choice
for end-stage renal disease also for patients with AAV.
Transplanted AAV patients exhibit a survival equal or superior to
patients with other renal diseases, and very few grafts are lost due
to recurrence of vasculitis.
Rate of relapse seems to be lower after transplantation as compared
to dialysis
Changes in ANCA levels can help to distinguish relapses from other
causes of graft dysfunction.
Relapses should be treated with increases in immunosuppressives,
but the best way to tailor therapy remains unknown
2013, La Médicale, (42), 4, 568-571.

Treatment protocols included:
Before ESRF and Tx:
Methyl prednisolone, Prednisolone
Cyclophosphamide
Azathioprine
Mycophenolate
Cyclosporin
Tacrolimus
Rituximab

Immunosuppressive protocols:
At & After Tx:
Basiliximab, Daclizumab, Alemtuzumab, ATG
Methyl prednisolone
Prednisolone
Azathioprine
Mycophenolate
Cyclosporin
Tacrolimus
IVIG
Rituximab
Bortezomib
Cyclophosphamide in relapse

Case Reports, Exp Clin Transplant, 2008 Jun;6(2):137-43.
Parvovirus B19 microepidemic in renal transplant
recipients with thrombotic microangiopathy and
allograft vasculitis
Mohammad R Ardalan1, Mohammadali M Shoja, R Shane Tubbs, David Jayne
Abstract: Parvovirus B-19 (B-19) can lead to various clinical scenarios in renal transplant recipients.
Here, we report a B-19 microepidemic that occurred between January and March 2007, involving renal
transplant recipients from a single center in Tabriz, Iran. We observed 6 patients in whom there was a
temporal association between active B-19 infection and thrombotic microangiopathy and intrarenal
small and medium-sized vessel vasculitis. Patients typically presented with deteriorating renal allograft
function and anemia, and laboratory findings revealed thrombotic microangiopathy. Ultimately, extensive
endothelial injury and renal allograft vasculitis that mimicked a vascular rejection ensued. In conclusion, B-
19-related thrombotic microangiopathy may precede allograft vasculitis in renal transplant recipients. A
high index of suspicion is required for early diagnosis and treatment of B-19 infection. To the best of our
knowledge, this series represents the first report of B-19-related renal allograft vasculitis in the English
literature

Our experience in Labbaf Hospital:
5 diagnoseded patients: 1 Lupus, 1 Wegener, 3 RPGN due to vasculitis
sex age date of Tx BG donor donor age primary dis pred cyclosporin cellcept Last Cr
F 13 12/18/1393 A- DD-f 20 SLE + cyclosporin +
F 13 3/4/1394 A+ DD-m 18 RPGN + cyclosporin +
F 9 3/27/1394 B+ LUR-m 24 wegener + cyclosporin + 0.68
M 13 10/15/1394 A+ LUR-m 34 RPGN + cyclosporin + ATG
M 14 4/21/1395 A+ LUR-f 35 RPGN + prograf + 2.48

Our recent experience(1):
Rasoul. 14 year old boy admitted in our emergency ward for respiratory compromise and high BUN,
Cr and Hematuria and Proteinuria.
U/A: Hematuria, Proteinuria 3+
His C3: 0.8, C4: O.2, CH50: 53, ANCA P: 8 C: 3
Rising his BUN, Cr course showed RPGN and he underwent renal Biopsy
Biopsy showed: Crescentic GN
He received pulse methyl prednisolone and cyclophosphamide and plasma exchange
But eventually went to ESRF due to RPGN secondary to ANCA Associated Vasculitis (AAV)
with panel reactivity of 10%
At Tx RBC: 3-4, WBC: 8-10, Protein 1+
In 21.4.95 he underwent kidney transplantation from LURD
Donor was a 35 yr lady Donor and Recipient BG = A+

Our recent experience(2):
Rasoul:
Baseline Cr after Tx : 0.9 mg/dl
Cr in 25.8.95 (4month after Tx); 1.1 mg/dl
Immunosuppression:
Prednisolone
Cyclosporine  Tacrolimus
Mycophenolate Mofetil (Cellcept)
Sudden rise in Cr in: 1.7.98  Tx Biopsy

Our recent experience (3):
Rasoul:
Tx Biopsy in 6.7.98 Revealed: Chronic active AMR ,
MPGN pattern
He received: Rituximab, IVIG 60 gr, Plasmapheresis and
Plan was if rising DSA Bortezomib
Last visit: 29.2.99 Cr is 2.48 mg/dl

Our recent experience (4):
Reyhaneh: shared with Dr Shiari
Wegener`s DOB: 30.3.85
Presented in 30.10.86  with Anemia, Cr↑, ↑ Echo kidneys
Renal biopsy showed: Secondary FSGS
Tx in: 26.3.94
Immunosuppressions are: Pred 7.5 mg/day.
CyA, Cellcept
Last visit: 10.4.99 Cr is 0.68 mg/dl

Our Challenges and limitations:
No protocol biopsy
Even hesitation of parents to biopsy when critical
Non-compliance in teenagers and disagreement
for biopsy
So may miss recurrence and treat as rejection

Renal transplant vasculitis

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