Approximately 10 to 30 percent of patients with proliferative lupus nephritis progress to end-stage renal disease (ESRD), depending upon the severity of the disease, ancestral and socioeconomic factors, noncompliance, and the response to initial treatment. Overall prognosis has improved in recent decades, perhaps due to the use of combined immunosuppression .

1. Renal Transplantation Among Patients With
Lupus Nephritis
By
S .T. Esfahani, MD
Emeritus Professor of Pediatrics
Tehran University of Medical Sceinces

2. Renal Transplantation in SLE
Introduction
o Approximately 10 to 30 percent of patients with proliferative lupus nephritis
progress to end-stage renal disease (ESRD), depending upon the severity of the
disease, ancestral and socioeconomic factors, noncompliance, and the response to
initial treatment.
o Overall prognosis has improved in recent decades, perhaps due to the use of
combined immunosuppression .

3. Choosing RRT in patients with LN and ESRD
Current practice for those who progress to ESRD as a result of exacerbation of lupus
nephritis or newly diagnosed lupus with rapidly progressive renal disease is to start
with hemodialysis (HD).
The rationale is to suppress any residual lupus activity, to allow the disease to
become quiescent, mostly in those patients who experience a rapid decline in renal
function due to aggressive lupus.

4. Choosing RRT in patients with LN and ESRD
o Remission of lupus overall is particularly important before proceeding to
transplantation, and thus, all patients with recent significant renal or extra-renal
activity and ESRD begin with HD.
o One potential benefit from this choice is the believed “burn-out” effect of this
modality on the disease.
o Secondly, 3 to 6 mo on dialysis, before proceeding to transplantation, seem to be
sufficient for renal function to recover in individuals with rapidly progressive
glomerulonephritis due to lupus.
o In contrast, patients who are in complete remission for a considerable time period
prior to ESRD, may also precede with preemptive KTX, if there is an appropriate
living donor.

5. Choosing RRT in patients with LN and ESRD
This practice is supported by analysis of the United Network for Organ Sharing dataset
from 1987 to 2009, which revealed that patients with lupus nephritis who received a
kidney transplant preemptively, before the need for dialysis, presented better graft
survival and a lower risk of recipient death. It was associated with superior patient and
graft outcomes.
Costenbader Khet al: Trends in the incidence, demographics, and outcomes of end-stage renal disease due to
lupus nephritis in the US from 1995 to 2006. Arthritis Rheum 2011; 63: 1681-1688

6. Choosing RRT in patients with LN and ESRD
Finally, PD is a better choice for initiating renal replacement therapy in patients
with lupus and antiphospholipid syndrome, since access failure due to
recurrent thrombosis is a major problem in this group of patients.

7. PROGNOSIS IN DIALYSIS PATIENTS
Patient survival with either hemodialysis or continuous ambulatory peritoneal
dialysis appears to be similar to that in the general population of patients with
ESRD.
Bomback AS ET al: End-stage renal disease due to lupus nephritis.
Up To Date 2020

8. RENAL REPLACEMENT THERAPY FOR LUPUS
PATIENTS WITH ESRD: KTX, PD or HD ?
A clear superiority of KTX, in terms of survival and complication rates, has been shown
in a retrospective multicenter study . Ten year survival in 59 individuals, who
underwent KTX, PD or HD for lupus nephritis, was 90%, 81% and 55%, respectively.
USRDS: Between 1995 and 2006, 12344 patients with ESRD related to lupus nephritis
were identified. Hemodialysis was the most commonly used renal replacement therapy
with a significant increase during the study period (from 75.9% to 83.9%).
KTX rates decreased markedly from 1995 to 2006, a fact that could be associated with
donor organ shortage and the low socioeconomic status of several patients.
Costenbader KH, et al, Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus
nephritis inthe US from 1995 to 2006. Arthritis Rheum 2011; 63: 1681-1688

9. LUPUS ACTIVITY IN PATIENTS WITH ESRD
The development of ESRD is, in many patients, associated with gradual complete or partial
resolution of the extrarenal manifestations of lupus. How this occurs is not well understood.
Longstanding clinical experience and research have shown that patients with renal failure
resulting from lupus frequently experience a remission of their extra-renal manifestations
and improvement in lupus serologic results with dialysis so that all immunosuppression can
be withdrawn.
This quiescence of lupus in patients with ESRD and is termed “burnt-out lupus ‫شدن‬ ‫خاموش‬ ”.

10. LUPUS ACTIVITY IN PATIENTS WITH ESRD
o Although the causes of this phenomenon are not completely understood, it is
repeatedly reported and in many cases associated with gradual or partial
resolution of the extra-renal manifestations of lupus.
o Less frequently, and typically in patients of black race, some investigators have
reported continuation of lupus activity and occasionally exacerbation with the
onset of ESRD.
Ponticelli C, Moroni G. Renal transplantation in lupus nephritis. Lupus 2005; 14:95.
Bomback AS ET al: End-stage renal disease due to lupus nephritis. Up To Date 2020

11. ASSESSMENT OF DISEASE ACTIVITY AND SEVERITY
o Determining the appropriate therapeutic regimen requires an accurate assessment
of both disease activity and severity and a clear understanding of the patient's
response to previous and ongoing therapeutic interventions .
o It is also important to assess for the wide range of disease manifestations.
o Disease activity refers to the manifestations of the underlying inflammatory process
at a point in time in terms of magnitude and intensity.
o The disease severity refers to the type and level of organ dysfunction and its
consequences, often described as mild, moderate, and severe. The degree of
irreversible organ dysfunction has been referred to as damage.

12. ISSUES RELATED TO KIDNEY TRANSPLANTATION
Patient and allograft survival :
Kidney transplantation has been associated with improved survival among patients
with ESRD due to lupus nephritis .
Most, but not all , studies have found that overall 5- and 10-year graft survival rates are
similar among patients with lupus compared with those in patients with other
diseases.

13. KDIGO Clinical Practice Guideline on the Evaluation and
Management of Candidates for Kidney Transplantation
o Cause of ESKD in candidates should be determined where possible to inform risks and
management after kidney transplantation
o Candidates with primary focal segmental glomerulosclerosis (FSGS), membranous
nephropathy, IgA nephropathy, IgA vasculitis, immune complex-mediated
membranoproliferative glomerulonephritis, C3 glomerulopathy, lupus nephritis,
antiphospholipid syndrome, ANCA-associated vasculitis, anti-GBM disease, hemolytic
uremic syndrome (HUS), atypical HUS, fibrillary or immunotactoid glomerulonephritis,
correctable hyperoxaluria, or those with cystinosis, Fabry disease, sickle cell disease,
sarcoidosis, Alport syndrome, systemic sclerosis or AA amyloidosis with no severe
extrarenal disease, should not be excluded from transplantation.
o However, the risk of recurrence should be considered and discussed with the candidate.
Transplantation 2020;104: 708–714.

14. Timing of transplantation
o It has been recommended that all patients with ESRD due to lupus nephritis be
dialyzed for at least three to six months and be on less than 10 mg of prednisone per
day before kidney transplantation is performed, particularly among those with
relatively rapid progression to ESRD.
o There are two potential advantages to this regimen: It may lead to a further reduction
in lupus activity, and it gives patients with relatively acute renal failure time to recover
sufficient renal function for dialysis to be discontinued, which removes the indication
for transplantation.
o However, a period of dialysis is not necessary for patients with a slow, progressive
course to ESRD who have been shown to have only chronic sclerosing lesion on kidney
biopsy and who exhibit no clinical or serologic activity. Such patients often undergo
preemptive kidney transplantation.

15. Immunosuppressive therapy for anti-rejection
 Induction and maintenance immunosuppressive regimens to prevent rejection are
the same among patients with ESRD from lupus nephritis as among patients with
other forms of renal disease, although the use of glucocorticoid-free regimens
among patients with ESRD due to lupus nephritis is not standard practice.
 Moreover, considerations of prior therapies for lupus nephritis (eg, prior
cyclophosphamide and other immunosuppressives) may influence the risk of
transplant marrow suppression and infections such as progressive multifocal
leukoencephalopathy (PML).

16. Recurrent lupus nephritis : Incidence
• The reported rate of clinically apparent recurrent lupus nephritis in the kidney transplant
is 2 to 11 percent.
• In the largest reported series, the frequency and outcome of recurrence was analyzed
using data from the United Network for Organ Sharing (UNOS) files . Among 6850
patients with ESRD due to lupus nephritis who received a transplant between 1987 and
2006, 167 (2.4 percent) had recurrent lupus nephritis *.
• The rate of recurrent symptoms of systemic lupus is also low, at approximately 6 percent
These low rates are thought to reflect diminished immunologic activity.
* Contreras G, Mattiazzi A, Guerra G, et al. Recurrence of lupus nephritis after kidney transplantation. J Am
Soc Nephrol 2010; 21:1200.

17. Clinical presentation and biopsy findings
 Patients with recurrent lupus nephritis generally present with an increased serum
creatinine above their usual baseline, new-onset or worsening proteinuria of a
variable degree, and new-onset hematuria on routine screening.
 Recurrent lupus nephritis can occur as early as the first week to as late as 16 years
after transplantation (median 4.3 years in the large study cited above), with most
episodes occurring during the first 10 years.
 On biopsy, the histologic lesion may be different and is often less severe from that
observed in the native kidney.
Contreras G, Mattiazzi A, Guerra G, et al. Recurrence of lupus nephritis after kidney transplantation. J Am Soc Nephrol
2010; 21:1200.

18. CLINICOPATHOLOGIC CORRELATIONS
o Incidence rates of “subclinical” lupus nephritis in the allograft, i.e., histopathological
findings in protocol or serial biopsies, differed substantially from those which were
performed solely according to clinical indication. When both immunofluorescence and
electron microscopy were used for the evaluation of renal biopsies, along with a more
aggressive protocol of graft biopsies, it was shown that 30% of the patients
experienced recurrence of lupus nephritis. Time to RLN may also vary from days to
decades after KTX.
o Moreover, the histopathologic lesion may be different from the one in the native
kidney, and most frequently is less severe.
o Nevertheless, given the silent nature of many of the recurrences, it is impossible to
determine the precise timing of recurrence, or the rate of recurrence in patients who
did not undergo biopsies.

19. RISK FACTORS FOR RECURRENT LUPUS NEPHRITIS
The importance to practicing nephrologists of lupus recurrence in the renal graft is that
these patients may have poorer outcomes compared with other kidney transplant
recipients.
Recognized risk factors for allograft loss in lupus patients include black non-Hispanic
ancestry, female gender, and young age. Patients with antiphospholipid autoantibodies and
those receiving the kidney from living donors also have a higher risk of recurrence.
Recurrent lupus nephritis and chronic rejection of the kidney were shown to be risk factors
for allograft loss. However, Stone et al had found that RLN did not invariably result in
allograft failure.
Stone JH, et al. Outcome of renal transplantation in systemic lupus erythematosus.
Semin Arthritis Rheum 1997; 27: 17-26

20. DIAGNOSIS OF RLN IN THE ALLOGRAFT
o RLN in the allograft should be suspected in any patient who progresses to ESRD due to
renal lupus, in the light of certain clinical and/or laboratory findings.
o Thus, new onset proteinuria or glomerular hematuria should directly lead to the suspicion
of lupus nephritis in the allograft.
o However, rapid worsening of previously existing proteinuria should also raise the suspicion
for RLN, especially with the coexistence of glomerular hematuria.
o The clinical presentation of increased serum creatinine is also typical of patients with RLN
in the graft.

21. DIAGNOSIS OF RLN IN THE ALLOGRAFT
o However, among all transplant recipients who present with an elevated serum
creatinine, there are certain other parameters that need to be excluded as possible
contributors before considering a diagnosis of RLN.
o These include dehydration, toxic concentrations of serum calcineurin inhibitors,
and obstructive uropathy.
o Diagnosis of RLN is made by biopsy and histopathologic evaluation by light
microscopy, immunofluorescence and electron microscopy as discussed earlier.
o Measurement of serologic parameters, such as complement levels and titers of
anti-double stranded DNA antibodies is not helpful in establishing the diagnosis in
the RLN.
Up to date 2020

22. DIAGNOSIS OF RLN IN THE ALLOGRAFT
o Among all transplant recipients who present with an elevated serum creatinine, we
first ensure adequate hydration, measure a serum calcineurin inhibitor concentration,
and obtain a Doppler renal ultrasound with evaluation for renal artery stenosis and to
exclude hydronephrosis or other anatomic abnormalities prior to performing a
biopsy.
o Among patients who are well hydrated and have a normal calcineurin inhibitor
concentration and ultrasound, we perform a biopsy.
o In addition, among transplant recipients who have a history of lupus nephritis, we
perform a renal biopsy in the setting of new-onset proteinuria or hematuria once
urinary tract infection has been excluded by culture.
Up to date,2020

23. Treatment of recurrent lupus nephritis
Treatment consists of both nonimmunosuppressive and
immunosuppressive therapies.

24. Nonimmunosuppressive treatment of recurrent nephritis
 We generally treat all patients who have histopathologic changes of recurrent lupus
nephritis and proteinuria that is >300 mg/24 hours with renin-angiotensin system
(RAS) blockade.
 The rationale for treating with RAS inhibition is based upon studies in nontransplant
patients with proteinuric chronic kidney disease (CKD) that have shown that RAS
inhibition decreases the progression of renal disease.
 Most studies are of angiotensin-converting enzyme (ACE) inhibitors, but it seems likely
that angiotensin receptor blockers (ARBs) have a similar renoprotective effect as ACE
inhibitors in nondiabetic CKD.
Up to Date,2020

25. Nonimmunosuppressive treatment of recurrent nephritis
 The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest the
addition of an ACE inhibitor among patients with CKD and albumin excretion >300
mg/day .
 ACE inhibitors and ARBs may cause hyperkalemia and decreased perfusion among
transplant recipients. ACE inhibitors can also induce anemia in transplant recipients .
 However, given that transplant recipients are generally closely followed and such side
effects would be readily detected, the potential benefit of RAS inhibitors in delaying
the onset of ESRD among proteinuric patients outweighs the potential risk of a
reversible decline in eGFR, hyperkalemia, or anemia.
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl
2013; 3:5.

26. Antiphospholipid antibodies
 Lupus patients should be screened for the presence of antiphospholipid antibodies
prior to kidney transplant as kidney transplant recipients with underlying lupus who
have antiphospholipid antibodies may be at increased risk for thrombotic events.
 Patients with thromboembolic events should be treated with anticoagulation
therapy, using a regimen similar to that for symptomatic antiphospholipid syndrome
in general. The optimal therapy of patients with antiphospholipid antibodies but no
history of a thrombotic event is not well defined.

27. Immunosuppressive treatment of recurrent nephritis
 Most patients with recurrent lupus nephritis, particularly those who have mild lesions
on allograft biopsy, do not require any change in the immunosuppressive regimen that
they use to prevent rejection.
 Selected patients may require immunosuppressive therapy directed at recurrent lupus
nephritis. Among patients who have a histologic diagnosis of recurrent lupus nephritis
and rapid deterioration of kidney function that cannot be explained by other factors
such as chronic allograft nephropathy, cyclosporine toxicity, or acute rejection, or who
have proteinuria >500 mg/day accompanied by severe proliferative lesions on biopsy,
alter the immunosuppressive regimen that the patient is on for rejection prevention in
order to treat recurrent disease.

28. Immunosuppressive treatment of recurrent nephritis
Treatment options include using one of the following:
● Increase the dose of mycophenolate mofetil to 2 to 3 g/day.
or
● Administer cyclophosphamide and discontinue the current antimetabolite (which
is usually mycophenolate mofetil/sodium or azathioprine).

29. Immunosuppressive treatment of recurrent nephritis
 Patients that are treated with an increase in the mycophenolate dose or with the
addition of cyclophosphamide should also be treated with an increase in
glucocorticoids. We generally give methylprednisolone 7 mg/kg/day (or 500 mg)
intravenously for three days followed by a tapering oral glucocorticoid regimen.
 For patients who have failed treatment with both mycophenolate and
cyclophosphamide, some clinicians give rituximab (given on days 1 and 15) in addition
to increasing mycophenolate to 3 g/day and increasing glucocorticoids (ie,
methylprednisolone 7 mg/kg/day or 500 mg daily for three days followed by a tapering
oral glucocorticoid regimen), although this approach is not evidence based.
 The optimal dose of rituximab for recurrent lupus nephritis is not known, some centers
use the US Food and Drug Administration (FDA) recommended dose for antineutrophil
cytoplasmic antibody (ANCA)-associated glomerulonephritis (375 mg/m2 per week for
four weeks.
Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J
Med 2010; 363:221.

30. Renal prognosis
 The incidence of graft loss due to recurrent disease is low, being less than 2 to 4 percent
over 5 to 10 years in most studies.
 This finding is consistent with the general decrease in lupus activity in patients who develop
ESRD and in the less severe histologic findings than in the original disease as most patients
have minimal mesangial (class I), mesangial proliferative (class II), or focal proliferative
glomerulonephritis (class III), not diffuse proliferative disease (class IV), which is the most
severe form of lupus nephritis and is associated with a worse prognosis.
 In addition, the majority of patients who develop impaired renal function have one or more
other histologic findings that could have contributed to progressive disease, including acute
rejection, chronic allograft nephropathy, and cyclosporine nephrotoxicity .