Recurrent IgA

nephropathy in kidney
transplant
Geoffrey K. Dube, MD
Associate Professor of Medicine
Columbia University
 Case presentation: recurrent IgA
nephropathy in the allograft
• 41 y/o man with ESKD secondary to IgA
• Diagnosed with IgA age 19 (native kidney biopsy unavailable),
progressed to ESKD age 24
• Received LDKT from mother, found to have recurrent IgA on
biopsy at 7-years (MEST-C score unknown), kidney failed from
antibody-mediated rejection 2 years later
• Received DDKT with positive donor-specific antibodies,
induction therapy with thymoglobulin, maintained on
tacrolimus, mycophenolate, prednisone
• Early rejection treated successfully, baseline Cr 1.7-2.0
• 5-years post-transplant: 1.2 g albuminuria, Cr 2.1.
• Biopsy: “diffuse mesangial proliferative GN with focal necrotizing
and crescentic features, consistent with recurrent IgA
nephropathy”, M1E1S1T1C1
 Overview
• What are the risk factors for recurrent IgA
nephropathy?
• What is the impact of recurrent IgA nephropathy
on transplant outcomes?
• How do we treat recurrent IgA nephropathy in the
allograft?
• If someone has recurrent IgA nephropathy in their
first transplant, what happens if they get a second
transplant?
 How frequently does IgA nephropathy recur?

• Early histologic recurrence can be

detected on protocol biopsies
• Ortiz et al.: 21/65 (32%) of
patients had recurrence on
protocol biopsy at a median of 7
months (range 2.2-25) post-
transplant; 52% had normal
urinalysis
• Histologic recurrence is more
common than clinically significant
recurrence
• TANGO cohort: 504 patients, 23%
recurrence rate at 15 years
(median time 3.4 yr); 42% Cumulative incidence of IgA recurrence in
recurrence rate among patients TANGO cohort. 19% at 10-years.
who were biopsied
• Graft loss from recurrent IgA
occurred in 7/82 (8.5%) of
recurrences
1. Ortiz et al. Nephrol Dial Transplant 2011. 2. Uffing et al.
CJASN 16:1247-1255, 2021.
 Risk factors for recurrent IgA nephropathy

• Younger age at transplantation

• Kavanagh et al.: 282 patients – age at Tx 36 yr recurrence vs. 45 yr no
recurrence, aHR 0.96/year
• TANGO cohort: 504 patients – age at Tx 41 yr recurrence vs. 46 yr no
recurrence
• Rapid progression of native IgA
• TANGO cohort: time from diagnosis to ESKD 48 m vs. 72 m
• Presence of crescents on native kidney biopsy
• Columbia: 14 recurrences: 93% ≥10% glomeruli with crescents; 48 non-
recurrences: 42% had ≥10% glomeruli with crescents. HR for recurrence
1.21 per 10% increase in crescents
• Subclinical IgA deposits in the donor kidney
• Transplant era (recurrence less common in more recent years)
1. Kavanagh et al. Glomerular Dis 2(1):42-53, 2022. 2. Uffing et al. CJASN 16:1247-1255, 2021. 3. Avasare et al. Am J Nephrol 45:99-
106, 2017. 4. Wyld and Chadban Transplantation 100:1872-1832, 2016.
 Can HLA factors identify patients
at risk for recurrent IgA?
• Recurrence ↑in HLA 0-mismatch live donor kidney
• ANZDATA registry – 1354 patients with IgA transplanted 1987-2004.
• Recurrent disease in 7% overall but 17% of patients who received a 0-mm
LRT (HR 2.7); no difference in recurrence rates if 0-mm DDRT
• Graft survival for LDKT recipients equal with 0-mismatch and 1-6 mismatch
• Higher frequency of HLA-DQ5, lower frequency of HLA-DR15 and HLA-
DQ6 in patients with IgA
• Frequency of these alleles not different in recurrent vs. non-recurrent IgA
• Number of HLA matches associated with ↑risk of recurrence in LRKT
(aHR 1.4/HLA match) but not LUKT or DDKT
• Better HLA matching associated with improved transplant survival following
diagnosis of recurrent disease

1. McDonald and Russ. Transplantation 27:759-762, 2006. 2. Kavanagh et al. Glomerular Dis 2(1):42-53, 2022.
 Can serologic markers identify patients at
high risk for recurrence of IgA?
• Disease recurrence may be more common in patients with elevated
levels of galactose-deficient IgA
• Coppo et al. – 61 patients with IgA (30 with biopsy-proven recurrence
within 5-years): recurrence had borderline association with levels of
aberrantly glycosylated IgA1 (OR 8.2, p=0.077)
• Berthelot et al. – 60 patients with IgA (38 with recurrence): elevated Gd-
IgA1 associated with increased risk of recurrence (PPV 87%)
• Berthoux et al. – 96 patients with IgA (34 with recurrence): elevated Gd-
IgA1 not associated with risk of recurrence
• Meta-analyses have had conflicting results
• Other markers associated with ↑risk of recurrence in some studies
• Berthoux et al. - elevated levels of Gd-IgA1-specific IgG autoantibody were
predictive of recurrence
• Berthelot et al. – lower levels of IgA-sCD89 complexes
• Not currently monitored as standard of care in clinical practice

1. Coppo et al. Clin Transplant 21:728-737, 2007. 2. Berthelot et al. Kidney Int 88:815-822, 2015. 3. Berthoux et al. J Am Soc Nephrol
28:1943-1950, 2017. 4. Li et al. Front Immunol 2023 Nov 28:14:12770175. Gong et al. Transpl Immunol 2023 Aug:79:101850
 IgA nephropathy is associated with better
transplant outcomes than other forms of ESKD

Death-censored transplant survival, ANZDATA registry, 1998-2012.

2,395 patients with IgA vs. 36,918 patients with other causes of ESKD. (p=0.003)

Zhang et al. Nephrology 21(5):387-396, 2016.

 Long-term graft survival is inferior in patients
with IgA due to disease recurrence, especially
if proteinuric

TANGO cohort: 108 patients with recurrent IgA, graft

180 pts with IgAN compared with 360 non-diabetic survival by clinical presentation.
controls, 1981-2010. • HR for graft failure 3.7 with recurrence.
15-year DCGS 62.6% IgAN vs. 72.4% controls • 10-year DCGS: 89% vs. 76%
15-year DCGS 51.2% recurrent IgAN vs. 68.3% non- • Graft survival after diagnosis of recurrence:
recurrent IgAN • 1-year 94%, 5-year 83%, 8-year 68%
Mayo: Graft failure RR 3.4 if recurrent disease 1. Moroni et al. Nephrol Dial Transplant 28:1305-1314, 2013. 2.
Cosio and Cattran. Kidney Int 91:304-314, 2017. 3. Uffing et al.
CJASN 16:1247-1255, 2021.
 Steroid withdrawal is associated with an
increased risk of recurrent IgA and increased
risk of graft loss from recurrent disease
Re c urre nt IgA on Ma inte na nc e Ea rly s te roid
biops y pre dnis one withdra wa l

1-year 1.6% 1.6%

5-year 3.3% 8.8%

7-year 5.2% 22%

Minnesota: 66 patients with IgA transplanted

on early steroid withdrawal protocol, compared
with 65 historic controls maintained on
prednisone. ANZDATA: 1521 recipients with IgA who
• All recurrences were clinical (no protocol received a 1st transplant
biopsies). • 10-year incidence of graft loss from
• Similar patient and allograft survival. recurrent IgA was 4.3%; steroid use was
Meta-analysis: RR 3.33 for disease recurrence if associated with reduced risk of graft loss
steroid-free regimen. from recurrent disease (HR 0.5)
1. Kukla et al. Transplantation 91:1386-1391, 2011. 2. Sani et al. Transpl Immunol 80:101878, 2023. 3. Clayton et al. Am J Transplant
11:1645-49, 2011.
 Despite the lower risk of recurrent IgA,
maintenance prednisone not associated with
improved graft survival

UNOS, 2000-2014, use of steroids at hospital discharge among LDKT and DDKT recipients.
• No difference in overall patient or graft survival.
Aydin-Ghormoz et al.: UNOS analysis, 2000-2020. 11,341 patients with IgA treated with CNI + MMF +/-
prednisone – no difference in DCGS. Among DDKT recipients induced with rATG, maintenance
prednisone associated with ↓DCGS.
1. Leeaphorn et al. Transplant International 31:175-186, 2018. 2. Aydin-Ghormoz et al. Clinical Transplantation 2024;38:e15225.
 Do other immunosuppressive
choices impact risk of recurrence?
• Thymoglobulin associated with reduced risk of recurrence
• Berthoux et al.: 116 patients transplanted over 26-year period.
• Recurrence rate of 28% overall: 10.3% ATG, 28.6% IL2RB, 38.5% no
induction
• Alemtuzumab associated with increased risk of recurrence
• UNOS analysis, 2000-2020.
• In LDKT, OR 1.52 if maintenance prednisone, OR 1.56 if no
maintenance prednisone
• In DDKT, OR 1.9 if maintenance prednisone.
• Maintenance immunosuppression (not specific to IgA): risk of
graft loss from recurrent disease not affected by choice of
calcineurin-inhibitor (cyclosporine vs. tacrolimus) or anti-
metabolite (azathioprine vs. mycophenolate)

1. Berthoux et al. Transplantation 85:1505-1507, 2008. 2. Aydin-Ghormoz et al. Clinical Transplantation 2024;38:e15225. 3. Mulay et al.
Am J Transplant 9:804-811, 2009.
 Does pathology predict prognosis after
diagnosis of recurrent IgA nephropathy?
HR for graft failure:
• 1.69 if MEST-C = 1
• 8.57 if MEST-C = 2-3
• 61.32 if MEST-C = 4-5

Endocapillary hypercellularity,
IFTA, crescents associated
with ↑ risk of graft failure
• If E present, aHR 6.8
• If T present, aHR 5.9
• If C present, aHR 7.3

Association between sum of MEST-C score and

graft failure, from time of biopsy.

Alachkar et al. Transplantation 107:2055-2063, 2023.

 How do we manage recurrent IgA
nephropathy?
• No prospective studies of treatment of recurrent IgA
• KDIGO recommendations for treatment of native kidney IgA
• First-line treatment is optimized supportive care with ACEi/ARB
• Consider immunosuppression with glucocorticoids only if high-risk
for progression( >0.75-1 g/d proteinuria despite >90 d optimized
supportive care) and eGFR above 30
• Dilemma: all patients with recurrent IgA have recurred
despite treatment with immunosuppression
• No guidelines on what criteria to use to guide decision to
treat with increased immunosuppression or which
treatment regimen to use
• Most nephrologists treat with steroids and/or other IS agents based
on extent of proteinuria and histologic changes

1. KDIGO 2021 Clinical Practice Guideline for Management of Glomerular Diseases. 2. Hass et al. Kidney Int Rep 2023.
 Glucocorticoids for treatment of recurrent IgA
nephropathy
• Steroids
• Messina et al.: 29 patients from 2005-2012, 16 received pulse
steroids + prednisone. Most also received RAASi. Steroid
group with lower Cr and less proteinuria at last follow-up but
no difference in 5-year graft survival.
• Matsukuma et al.: 7 patients from 2013-2015 received pulse
steroids + 6-m prednisone taper. 6/7 achieved proteinuria
remission with stable Cr.
• Targeted-release budesonide
• Lopez-Martinez et al.: 5 patients with recurrent IgA treated
with enteric budesonide. Proteinuria ↓27% at 3-m, ↓61% at
6-m, ↓15% at 24-m. eGFR stable. No AEs attributable to
budesonide.
• Gandolfini et al.: 10 patients with recurrent IgA treated with
enteric budesonide. No evidence of proteinuria reduction,
eGFR stable.
1. Messina et al. J Nephrol 29:575–583, 2016. 2. Matsukuma et al. Nephrology 23(Suppl2):10-16. 2018. 3. Lopez-Martinez et al.
Transpl Int 35:10693, 2022. 4. Gandolfini et al. Kidney Int 130(5):1995-1996, 2023.
 Non-immunosuppressive therapies for
treatment of recurrent IgA nephropathy
• RAAS blockade
• First-line therapy for native kidney IgA, limited data with recurrent IgA
• ACEi/ARB ↓albuminuria in KTRs with > 1g/d
• Courtney et al.: 3/9 pts with RAASi progressed to ESKD vs. 4/4 pts
without RAASi
• TANGO cohort: 75% treated with ACEi/ARB, no difference in graft
survival
• SGLT2 inhibitors
• Use in native kidney IgA associated with ↓albuminuria and ↓likelihood
of eGFR decline
• No data to-date in recurrent IgA but SGLT2 inhibitors safe to give to
KTRs
• Sparsentan
• Use in native kidney IgA associated with ↓albuminuria and ↓likelihood
of eGFR decline
• No data to-date in recurrent IgA

1. Altiparmak et al. Transplant Proc 33(7-8):3368-3369, 2001. 2. Courtney et al. Nephol Dial Transplant 21:3550-3554, 2006. 3. Uffing et al.
CJASN 16:1247-1255, 2021. 4. Wheeler et al. Kidney Int 100:215-224, 2021. 4. Rovin et al. Lancet 402:2077-2090, 2023.
 Outcomes with retransplant in patients
with prior graft loss from recurrent IgA
• South Korea: 28 patients with graft failure from recurrent
IgA received a second transplant
• Recurrent IgA occurred in second transplant in 2 patients at 61
months follow-up
• Graft survival comparable to the first transplant
• ANZADATA Registry: among repeat transplant recipients,
rates of recurrent IgA were 10.6% in patients with disease
recurrence in the first kidney and 8.6% in patients without
disease recurrence in the first kidney (RR 1.24, p=ns).
• TANGO cohort: 70 patients with prior transplant, 23 with
graft failure due to IgA (+/- rejection)
• Recurrence rate 17% (vs. 15% among primary transplant recipients)
1. Baek et al. Clin Nephrol 86:87-93, 2016. 2. Jiang et al. BMC Nephrology 19:344, 2018. 3. Uffing et al. CJASN 16:1247-
1255, 2021.
 IgA vasculitis and kidney
transplant
• Histologic recurrence is common
• Thervet et al.: 13 patients received 18 transplants, recurrence
in 61% of transplants – subclinical in 10/11 cases
• Clinical recurrence less common
• Kanaan et al.: clinical recurrence in 5/43 (12%)
• Risk of recurrence 2.5% 5-years, 11.5% 10-years
• Risk of graft failure from recurrence 2.5% at 5-years and 7.5%
at 10-years
• Graft survival similar in IgAV compared with patients
with other causes of ESKD
• UNOS analysis: DCGS 5/10 years – 80% vs. 79%, 59% vs. 55%
1. Thervet et al. Transplantation 92:907-912, 2011. 2. Kanaan et al. Clin J Am Soc Nephrol 6:1768-1772, 2011. 3. Samuel et al. Clin
J Am Soc Nephrol 6:2034-2040, 2011.
 Back to our case…
• Recurrent IgA 5-years post-transplant, M1E1S1T1C1
• ACE inhibitor increased (limited by hyperkalemia)
• Treated with prednisone x 6 months
• Developed steroid-induced diabetes requiring insulin
during taper
• Persistent albuminuria despite maximally tolerated dose
of ACR inhibitor; added SGLT2 inhibitor with 50%
decrease in albuminuria
• Albuminuria 766 mg, Cr 2.7 (was 2.2 before SGLT2
inhibitor started)
 Summary
• IgA nephropathy recurs in more than 20% of
transplants over time, with the risk of recurrence
persisting over the long-term
• Disease recurrence, especially if concurrent
proteinuria, is associated with decreased graft
survival (although overall transplant outcomes for
IgA remain excellent)
• Disease recurrence may be more common in
patients not on maintenance prednisone, although
this does not seem to impair overall graft survival