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