Kidney Transplantation in Lupus Nephritis and Antiphospholipid
Syndrome
Saúl Pampa Saico
Hospital Ramón y Cajal, Madrid, Spain
Hospital Rey Juan Carlos, Mostoles, Madrid, Spain
Alcalá de Henares University, Alcalá, Madrid, Spain
Lupus nephritis is a major complication of
systemic lupus erythematosus (SLE) and is a
main factor of morbidity and mortality.
Maroz et al. Am J Med Sci 2013;346(4):319–323.
1.6 cases per millon
4.9 cases per
millon
Incidence of LN-ESRD. U.S. Renal Data System(USRDS)
from 1996 to 2004 (N=9199 new case)
Risk Factors and Associations to Progression of
LN-ESRD
• African American, Hispanic ethnicity
• Younger age
• Male gender
• Lack access to medical care
• High serum creatinine levels at diagnostic of LN
• Nephrotic range proteinuria
• Anti-Ro antibodies, Low complement levels
• Pathology: MPGN (who Class IV), tubular atrophy
• Delayed Kidney biopsy and delay in treatment.
• Poor response to immunosupresive therapy
• Comorbidities: hypertension, DM, high body mass index.
Demographic
and racial factors
Serological
factors
Histopathological
factors
Sistemic Lupus Erithematous
End StageRenal Disease
KidneyTransplantation
PD?HD
Lupus Nephritis
40-50%
15%-20%
Kidney Transplantation is the optimal
treatment of choice for patients with
incident LN-ESRD
HOW MANY PATIENTS WITH SLE ARE TRANSPLANT?
WHICH IS THE BEST MOMENT TO TRANSPLANT?
WHICH INMUNOSUPRESSION TREATMENT RECEIVE?
HOW IS THE KIDNEY AND PATIENTS SURVIVAL AND
RISK FACTORS?
HOW IS THE RISK OF RECURRENCE?
HOW IS THE COMPLICATIONS AFTER TRANSPLANT?
PERSIST LUPIC ACTIVITY?
Chronic Kidney DiseaseSpanish Register of Glomerulonephritis
SLE 12%
Kidney biopsies/year 138
Incidence of 4 cases/pmp
www.senefro.org
- Dates from 1994 to 2013
- Kidney biopsies 21.988
- Hospital Centers 158
SLE
IgAN
MN
FSGS
other GN
All-Causes of dialysis in Spain
0
5
10
15
20
25
Incidence of SLE in dialysis: Ramón y Cajal Hospital
Patients in dialysis:1306
SLE: 22 (1,5%)
Register dates: 40 years
Incidence: 1 per millon of population
Incidence of Sistemic disease
in dialysis: 5.5%
Teruel JL. www.senefro.org
Transplant incidence in SLE
• USA dates : 2286/92844 (2.5%)
• Publish series
o 50/3274 ( Cairoli E,2014) 1.5%
o 2/995 (Celtik A, 2015) 1.2%
o 43/1717 (Pampa S, 2018 ) 2.5%
o Before 2000 (2,4%)
o After 2000 (2,5%)
o Less than 40 years old (5%)
WHICH IS THE BEST MOMENT TO TRANSPLANT?
• Lupus activity should be absent or low for a period of 3–6
months (EULAR/ ERA-EDTA) or 6–9 months (GEAS) to be
eligible for transplantation.
• Although ESRD is often associated with remission of
lupus activity, this is not universal and extrarenal lupus
flares can still occur; patients should be managed
accordingly.
Wilhelmus S. Lupus nephritis management guidelines compared. Nephrol Dial Transplant
(2016) 31: 904–913
PERSIST LUPIC ACTIVITY?
Reduction of activity Persistence of activity
Studies 15 9
Patients 436 195
0
20
40
60
1 2 5
Cheig
Szeto
Evolution of activity in two studies with follow-up
years
Mattos P, Mittermayer S. Clin Rheumatol. 2012 Jun;31(6):897-905
Disease Activity in SLE Patients with ESRD:
Systemic Review of the Literature
• The assesment of lupus activity in ESRD patients is not easy.
• Despite the introduction of more than 60 system to defining disease
activiy is inevitably arbitrary and is not totally validate in ESRD.
• Serological markers such as complement and anti-DNA are routinely
tested to asses disease activity . Reports of the correlation of disease
activity with serological markers in ESRD are conflicting.
• In the LN-ESRD population, serologic markers cannot reliably asses
disease activity.
• We recommend clinical alertness to the potential development of
extrarenal manifestations of SLE in ESRD patients
Maroz et al. Am J Med Sci 2013; 346 (4): 319-323
SLE activity with different therapies
0
1
2
3
4
5
6
7
8
0
10
20
30
40
50
60
70
80
90
%
HD
PD
KT
Activity index
Krane. Am J Kidney Dis 1999:872-879
Waitlist in dialysis and Allograft Survival
United network for organ (UNOS)
Analysis of the U.S. Renal Data System data from 1995
to 2006 (LN progression to ESRD) in 11,317 patients:
• 85% of these patients were initiated on HD.
• 12.2% were started on PD.
• 2.8% underwent preemptive kidney transplantation
at the onset of ESRD.
N=8001 United network data 1987-2009 LN-ESRD
730 Preemptive KT
7271 Dialysis before KT
Naveed A et al. Preemptive Kidney Transplantation in Systemic Lupus Erythematosus.
Transplantation Proceedings, 43, 3713–3714 (2011)
• Among 20 974 patients with ESRD due to LN, 9659 were placed on the
transplant waitlist; of these, 5738 received a transplant during the
study period and 3921 did not.
• A total of 2670 waitlisted patients died during follow-up
.
• Transplant was associated with a 70% reduction in risk for death
(adjusted HR, 0.30 [95% CI, 0.27 to 0.33]).
• The main reason for the overall reduction was fewer deaths due to
cardiovascular disease and infections.
• The authors concluded that timely referral for transplant could
improve outcomes for patients with LN due to ESRD.
Jorge A et al, Renal transplantation and survival among patients
with Lupus Nephritis A cohort study. Ann Intern Med 2019 doi:
10.7326/M18-1570.
WHICH INMUNOSUPRESSION TREATMENT
RECEIVE?
N=4222
3623 patients
45 studies
Induction
599 patients
8 studies
Manteinance
Palmer SC. Am J Kidney Dis. 2017
INMUNOSUPRESSION IN SLE
0
0,5
1
1,5
2
2,5
3
Induction
0R
A Efficacy
Palmer SC. Am J Kidney Dis. 70(3):324-336.2017
Manteinance
Palmer SC. Am J Kidney Dis. 70(3):324-336.2017
• The basic post-transplant immunosuppression for LN
patients does not differ from that normally used in
managment.
• Calcineurin inhibitor, mycophenolate mofetil and
prednisone seems to protect against clinically over
recurrent disease, but not against chronic allograft
nephropathy.
• In patients with LN recurrence, an intensification of
immunosuppression should be reserved for the
exceptional cases showing a severe (life
threatening) lupus flare-up because of the potential
risks of serious or lethal infection.
HOW IS THE KIDNEY AND PATIENTS SURVIVAL
AND RISK FACTORS?
HOW IS THE RISK OF RECURRENCE?
Patient Survival in SLE
10 years 89,9%
Global Kidney Evolution
RR 2.7 with respect to general
population
V: Zakharova. BioMed Research International 2016.
K.Manger. Ann Rheum Dis 2002;61:1065–107
CR 95%
PR 65%
NR 35%
Renal Survival in SLE
Global outcome at 15 years
76,3%
V. Zakharova. Bio Med Research International. 2016, ID 7407919
Complete remission 100%
Partial remission 58%
Not respond 0%
N=178
Graft Survival (%) Patient Survival (%)
Reference N 1 5 10
years
N 1 5 10
years
Moroni et al (2005) 35 - 85 76 33 97 97
Ghafari et al (2008) 23 - - 69 23 - - 83
Bunnapradist et al (2006) 1170 89(A) 68 (A) - 1170 94 (A) 85 (A) -
789 94 (B) 78 (B) - 789 98 (B) 92 (B) -
Yu et al () 23 95 73 57 23 95 95 95
Lionaki et al (2014) 26 88 67 38 26 92 77 77
Azevedo et al 48 93 81 - 45 98 91 -
Oliveira et al (2012) 14 93 91 86 14 96 95 94
Pampa et al (2018) 43 - 80 76 43 - 90 76
Notes: A Deceased donor; B living donor.
KT IN SLE: Graft and Patient survival
Chelamcharla M et al The outcome of renal transplantation among systemic
lupus erythematosus patients. Nephrol Dial Transplant (2007) 22: 3623–3630
Contreras G et al. Lupus (2012) 21, 3–12
Kidney transplantation outcomes in African-,
Hispanic- and Caucasian-Americans with SLE
Allograft survival Patient survival
Allograft Survival Patient Survival
Risk Factors of recurrence
Contreras G et al. J Am Soc Nephrol 21: 1200–1207, 2010
Recurrence of Lupus Nephritis after Kidney
Transplantation
Patients with
antiphospholipid
autoantibodies and
KT from
living donors have a
higher risk of
recurrence.
Kidney Transplantation and SLE Recurrence
Studies N Recurrence Graft Survival
Cairoli E 50 1(2%) 67% at 10 years
Pampa S 43 0 No diferencceswith PGN
Roozbeh J 33 0
Grumbert 60 0
Burgos P 177 20(11%) No differences
Moroni 8% No graft waslost becauserecurrence
UNOS 6850 167 (2,4%) Graft failuredue recurrence7%.
• The risk of recurrence lupus nephritis (LN) after renal
transplantation have been reported, ranging from 0% to 44%.
A different reasons:
1. The indication for renal allograft biopsy: Histological recurrence has
been reported in up to 30% of KT. Clinically recurrence disease occurs in
2–9%.
2. Diagnosis of recurrence of LN requires a graft biopsy examined by light
microscopy, immunofluorescence, and electron microscopy, which
were not always routinely performed.
3. The follow-up was short in many studies (recurrences may occur more
than a decade after transplantation).
HOW IS THE RISK OF RECURRENCE?
In summary, LN may recur after renal transplantation
but in most patients recurrence neither causes severe
histologic lesions nor has a relevant clinical effect on
the long-term outcome.
HOW IS THE COMPLICATIONS AFTER TRANSPLANT?
Patient complication Graft complication
Cardiovascular
disease
Infectious Disease
Neoplasm
Graft recurrence
Acute rejection
Chronic rejection
Arterial or venous
thrombosis
SLE is characterized by an accelerated atherosclerotic
mechanism. Several small, mostly retrospective, single-center
studies with limited numbers of patients indicate
cardiovascular disease as the leading cause of morbidity
and mortality in transplanted patients secondary to lupus
nephritis.
Costenbader K et al. Arthritis Rheum. 2011 June ; 63(6): 1681–1688
Cardiovascular disease
and SLE
UNOS Causes of death
.
• Transplant was associated with a 70%
reduction in risk for death (adjusted HR, 0.30
[95% CI, 0.27 to 0.33]).
• The main reason for the overall reduction was
fewer deaths due to cardiovascular disease
and infections.
Jorge A et al, Renal transplantation and survival among patients
with Lupus Nephritis A cohort study. Ann Intern Med 2019 doi:
10.7326/M18-1570.
• Infecctions (sepsis, pneumonia, viral infections, fungalinfections, tuberculosis, urinary tract infections) have been reported as causes of morbidity and mortality after KT due to lupus nephritis.
• Prolonged exposure to immunosuppressive agents prior to ESRD, as well after ESRD and KT predisposes to infections.
• However, published data are contradictory as the prevalence of serious infections is not always higher in SLE recipients compared with non-SLE patients.
Yu TM. Lupus 2008; 17: 687-694
Roman MJ N Engl J Med 2003; 349: 2399-2406
Chelamcharla M, Nephrol Dial Transplant 2007; 22: 3623-3630]
CONCLUSIONS
Renal involvement is a determinant of prognosis in patients
with SLE.
The evolution to End Stage Renal Disease usually accompanies
the decrease in lupus activity.
The duration of dialysis before transplantation and serological
status in the absence of clinically active disease do not predict
recurrence.
Kidney transplantation is the RRT modality with less lupus
activity and better survival , improves quality of life, reducing
complications and reduces health care costs.
Long-term patient and graft survival are similar to kidney
allograft recipients with other underlying diseases.
The usual immunosuppression of the transplant has activity
against SLE.
The evolution of patients and grafts in SLE is good with low
relapse rate of nephritis
Graft loss due to recurrent lupus nephritis is uncommon,
occurring in 2–4%.
CONCLUSIONS
Kidney Transplantation in Antiphospholipid Syndrome
• Antiphospholipid antibody syndrome (APS) is an acquired disorder
in which autoantibodies directed against phospholipid-binding
proteins are associated with vascular thrombosis and/or
pregnancy-associated morbidity (fetal loss).
There is growing evidence that patients with ESRD with antiphospholipid
antibody syndrome (APS) are at a high risk for renal vascular thrombosis,
graft failure and/or systemic thrombosis post-transplantation
Stone JH et al. Am. J. Kidney Dis. 1999; 34: 1040–47.
Vaidya S et al. Transplant. Proc. 1999; 31: 230–33.
Nzerue CM et al. Kidney Int 2002: 62: 733.
Morbidity after transplantation was similar in patients with
LN with aPL antibodies and in well-matched controls, with
the exception of thrombotic events (vascular and obstretic
manifestations) that were more frequent in LN.
Moroni G Antiphospholipid antibodies are associated with an increate risk for chronic
renal insufficiency in patients with lupus nephritis. Am J Kidney Dis 43: 28–36, 2004
Recent studies revealed that the presence of antiphospholipid antibodies alone negatively impacts 10-year graft survival, but the impact is not as large as the impact pretransplant history of APS.
SLE patients with history of APS have significantly lower long-term graft survival even while on anticoagulation and need to be monitored closely for thrombotic complications.
Vaidya S. Ten-yr renal allograft survival of patients with antiphospholipid antibody syndrome.
Clin Transplant 2012: 26: 853–856
Following renal transplant, patients with only circulating levels of
anticardiolipin antibodies (ACA) and no evidence of thrombosis have
just as good long-term allograft survival as those who have neither ACA
nor aPL antibodies.
Long term allograft survival of APS is not influenced by type of
anticoagulation.
• Treatment of APS in the context of SLE should not differ from treatment
of primary APS.
• HCQ may prevent the thrombotic complications in patients with
antiphospholipid syndrome and may be used safely during
pregnancy.
Vaidya S. Ten-yr renal allograft survival of patients with antiphospholipid antibody syndrome.
Clin Transplant 2012: 26: 853–856
Ponticelli C. Moroni. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin
Drug S. 2017 Mar;16(3):411-419
A recent meta-analysis supported a protective role of low-dose aspirin for
primary prophylaxis against thrombosis in the subgroup of aPL carriers
who had SLE.
Patients with SLE with aPL may also receive additional anticoagulant treatment,
such as low-molecular weight heparin, during high-risk periods for thrombosis
(pregnancy or postoperatively), although no studies have formally addressed
this question.
In patients with SLE-APS, use of novel oral anticoagulants for secondary
prevention should be avoided; however, they could potentially serve as an
alternative option in selected patients (low-risk aPL profile, no history of arterial
thrombotic events).
Arnaud L, et al .Autoimmun Rev 2014;13:281–91.
Bowman L, et al. N Engl J Med 2018;379:1529–39.
Ridker PM. N Engl J Med 2018;379:1572–4.
Pengo V, et al. J Thromb Haemost 2010;8:237–42.
Yes.
But………
Better remission in early phases
Kidney transplant in lupus nephritis:
Is it a therapeutic option?
Thank you for your
attention