related tubulointerstitial nephritis concurrent with

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Rajni Chibbar1 | Glenda R. Wright1 | Pouneh Dokouhaki1 | Sandi Dumanski2 |. Bhanu Prasad3 | Michael Mengel4 | Lynn D. Cornell5 | Ahmed Shoker4.

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Received: 14 November 2017    Revised: 16 March 2018    Accepted: 20 March 2018 DOI: 10.1111/ajt.14758

CASE REPORT

Recurrent IgG4-related tubulointerstitial nephritis concurrent with chronic active antibody mediated rejection: A case report Rajni Chibbar1 | Glenda R. Wright1 | Pouneh Dokouhaki1 | Sandi Dumanski2 |  Bhanu Prasad3 | Michael Mengel4 | Lynn D. Cornell5 | Ahmed Shoker4 1 Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 2

IgG4-related disease is a relatively newly described entity that can affect nearly any organ, including the kidneys, where it usually manifests as tubulointerstitial nephritis

Division of Nephrology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

(IgG4-TIN). The diagnosis can be suggested by characteristic histological features,

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ated with “storiform” fibrosis. Serum IgG4 is usually elevated. In the native kidney

Section of Nephrology, Department of Medicine, Regina General Hospital, Regina, Saskatchewan, Canada 4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 5

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada Correspondence Rajni Chibbar Email: [email protected] ca

including an inflammatory infiltrate with increased IgG4-positive plasma cells associand other organs, there is typically a brisk response to treatment with immunosuppression. Recurrence of IgG4-TIN after renal transplant has not been described in the literature. Here, we describe the first case of recurrent IgG4-TIN in a young patient concomitant with chronic active antibody mediated rejection five years after kidney transplant. Recurrent IgG4-TIN could be diagnosed by the characteristic histopathologic features and increased IgG4-positive plasma cells. Despite maintenance immunosuppression, this disease may recur in the kidney allograft. KEYWORDS

antibody-mediated (ABMR), clinical research/practice, kidney (allograft) function/dysfunction, kidney (native) function/dysfunction, kidney transplantation/nephrology, recurrent disease, rejection

1  | I NTRO D U C TI O N

IgG4-RD typically shows a brisk response to immunosuppression therapy, but has a high relapse rate. Perhaps because of this re-

IgG4-related disease (IgG4-RD) is an immune-mediated systemic

sponse to therapy, end-stage renal disease due to IgG4-TIN is rare.3

disorder that may involve nearly any organ system and has variable

However, in patients who develop end-stage renal disease, it has

clinical presentations. Commonly involved organs are pancreas, sal-

been unknown whether they would develop recurrent IgG4-TIN in a

ivary glands, lacrimal glands, kidney, lung, and retroperitoneal soft

kidney transplant in the setting of maintenance immunosuppressive

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tissue. Histologically, IgG4-RD is characterized by a dense lymph-

therapy.

oplasmacytic inflammatory infiltrate usually associated with “storiform” fibrosis. Immunoperoxidase staining shows increased IgG4 positive plasma cells and usually a high IgG4 to IgG positive plasma cell ratio.

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2 | C A S E

In the kidney, IgG4-RD usually manifests as tubulointer-

stitial nephritis (IgG4-TIN).4 Clinically, IgG4-TIN presents as acute or

A 25-year-old man was referred in 2008 to the Saskatchewan

chronic renal failure, renal mass lesion(s), or both. Most patients with

Kidney Transplant Program for assessment to undergo kidney trans-

IgG4-RD have high levels of serum IgG4 and some have hypocom-

plantation. He was known to have end-stage kidney disease due to

1–8

interstitial nephritis of unknown etiology since 2007. No specific

plementemia, particularly in those with renal involvement.

treatment was offered at the time of diagnosis of native kidney disAbbreviations: ABMR, Antibody mediated rejection; IgG4-RD, IgG4-related diseases; IgG4-TIN, IgG4 Tubulointerstitial nephtitis; PCCR, Plasma cell rich rejection; TCMR, T-cell mediated rejection.

Am J Transplant. 2018;1–5.

ease. The patient had a history of asthma and history of lymphadenopathy. Excisional biopsy of one of enlarged cervical lymph node

amjtransplant.com

© 2018 The American Society of Transplantation  |  1 and the American Society of Transplant Surgeons

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CHIBBAR et Al.

showed a benign reactive process and further characterization for

inflammatory infiltrate with numerous plasma cells, lymphocytes,

the nature of this process was not done. The patient also reported

and eosinophils (i3). Inflammatory infiltrate involved scarred and

swelling to the left submandibular region. A fine needle aspiration

nonscarred area. There was focal storiform fibrosis. Deposits

was performed. Cytological examination showed a polymorphous

were present in tubular basement membranes as seen by electron

population of lymphocytes and plasma cells with no representation

microscopy and immunofluorescence studies with IgG antibody.

of salivary gland tissue. There was no progression of the subman-

These tubulointerstitial findings were suggestive of recurrent

dibular disease, symptoms resolved and therefore it was not pursued

IgG4-TIN (Figure 2A-D). Immunostaining for polyoma virus (SV- 40

further. In retrospect, the patient likely had IgG4-RD with inflamma-

T antibody) was negative. There was no light chain restriction in

tory involvement of the kidney, lymph nodes, and salivary glands;

the plasma cells and EBER staining was negative.

many patients with IgG4-RD also have a history of allergy as this patient did.

Review of the native kidney biopsy performed in 2007 revealed morphological similarities of the tubulointerstitial inflammation in

The patient was determined to be a suitable candidate for kid-

the native and transplant biopsies, including a plasma cell–rich infil-

ney transplantation. Panel-reactive antibodies measured by ELISA

trate and storiform fibrosis (Figure 3A-D). Recognition of this histo-

were zero. The patient received a deceased-donor kidney transplant

logic pattern raised the suspicion for IgG4-TIN. Immunoperoxidase

in 2009, seven months after the initial transplant evaluation. The

staining performed for IgG4 and IgG demonstrated a marked in-

baseline allograft biopsy was normal. Induction therapy included

crease in IgG4 positive plasma cells throughout both biopsies (native

two doses of basiliximab and high-dose intravenous steroid as per

and transplant) and a high (>50%) IgG4 to IgG positive plasma cell

local protocol. The patient had initial good graft function without

ratio. Immune deposits were also noted in tubular basement mem-

evidence of early transplant rejection and had no surgical compli-

brane by IgG staining and dense deposits on electron microscopy in

cations. He was discharged home within one week. The discharge

both native and posttransplant kidney biopsies.

serum creatinine was 123 μmol/L and reached 108 μmol/L in the

The serum IgG4 levels performed in year 5 posttransplant

next three weeks. The patient was maintained on prednisone (5 mg

serum was elevated at 511 mg/dL (reference range 3.9- 86 mg/dL:

daily), tacrolimus to maintain a level of 6- 8 μg/L, and mycophenolate

Scarborough General Hospital, Scarborough, Ontario, Canada).

mofetil 2 g daily.

The native and transplant biopsies were referred to two pathol-

The patient remained stable until five years posttransplant, with-

ogists with expertise in the field of transplantation and IgG4-RD as

out evidence of medication nonadherence. At this point, on a routine

there were no reports of recurrence of IgG4-TIN after renal trans-

follow-up exam, the serum creatinine was found to be increased to

plantation in literature. The consensus diagnosis was chronic active

158-191 umol/L associated with increased proteinuria and urine al-

antibody mediated rejection (with severe transplant glomerulopa-

bumin/creatinine ratio of 47.5 mg/mmL. There was no evidence of

thy) and recurrent IgG4-TIN.

obstruction on ultrasound examination. Serum and urine BK viral

At the time of the biopsy of transplanted kidney, the PRA was

serology was negative. Donor-specific antibodies (DSA) against both

100% with strong reactivity against donor A1, 11, B8, 56, DR1,3, and

HLA class 1 and class 2 were found to be positive.

DQ 2 with median florescence index (MFI for total IgG) above 25 000.

A biopsy of the transplanted kidney was performed. Cortex

Over the following weeks, the patient received a total of 250 mg

and medulla were present, including eleven glomeruli, four of

thymoglobulin, 600 mg rituximab, high- dose steroids; 125 mg in-

which were globally sclerosed. The glomeruli showed features of

travenous immunoglobulin, and plasmapheresis. Plasmapheresis

severe transplant glomerulopathy (cg3) characterized by diffuse,

was continued for 51 treatments because of persistence of DSA

global basement membrane duplication. Segmentally capillary

and progressive allograft dysfunction. Unfortunately, the heavy im-

loops showed marginated mononuclear cells and focal near occlu-

munosuppression was complicated by CMV disease including CMV

sion of capillary lumen by endothelial cells and inflammatory cells

pneumonitis and recurrent bacterial infections, and so immunosup-

(g2). In addition, there was mild mesangial hypercellularity (mm1).

pression was reduced. Newer and potentially more effective treat-

Glomeruli did not show mesangiolysis or capillary loop thrombi.

ment such as anti- interleukin 6 receptor monoclonal antibody was

Peritubular capillaries were dilated and showed marginated mono-

not available.9 Over the following 12 months, the allograft failed and

nuclear cells (ptc2). Interstitial fibrosis and tubular atrophy af-

the patient returned to hemodialysis.

fected 20% of the sampled cortex (ct1, ci1, and i-IFTA 3). Rare tubules showed one to two mononuclar cells under the basement membrane (t1). There was no endothelialitis, or transmural vas-

3 | D I S CU S S I O N

cular inflammation (v0). Immunofluorescent studies demonstrated diffuse, bright C4d staining in peritubular capillaries (C4d 3+).

Here we present the first identified case of recurrent IgG4-TIN in

Electron microscopy showed enlarged endothelial cells and mul-

the renal allograft. The histologic and immunophenotypic features

tilayering of glomerular and peritubular capillary basement mem-

of the native kidney and transplant kidney biopsy are typical of IgG4-

branes (Figure 1A-F). These findings were diagnostic of chronic

TIN, and the patient had an elevated serum IgG4 level at the time of

active antibody mediated rejection. In addition, by light micros-

posttransplant kidney biopsy, which would be diagnostic of IgG4-

copy, there was a diffuse, moderate to focally marked interstitial

TIN in a native kidney.

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CHIBBAR et Al.

A

B

C

D

E

F

F I G U R E   1   Representative posttransplant kidney biopsy findings: 1A, 1B: Glomerulitis and transplant glomerulopathy with near occlusion of capillary lumen (1b: arrow) by mononuclear inflammatory cells (1A: X200 1a,PAMS: 1B; X400 PAS); 1C: peritubular capillaritis (X400, PAS); 1D: Diffuse, strong, circumferential C4d immunofluorescence staining of peritubular capillaries; 1E: electron microscopy: showing subendothelial widening by amorphous material and cellular debris, multilayering and reduplication of capillary basement membrane (×8000); 1E: electron microscopy showing peritubular capillary basement membrane multi-lamination (×8000)

IgG4-RD typically shows a brisk response to treatment with im-

(PTLD), plasma cell rich tubulointerstitial nephritis,10 and plasma

munosuppression, and indeed, response to steroids is a diagnostic

cell–rich rejection (PCRR). Interestingly, both BK-TIN and IgG4-TIN

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criterion for IgG4-RD. In the native kidney, approximately 90% of

can show tubular basement membrane immune complex deposits.8

patients with IgG4-TIN show a response to steroids or other immu-

In this case, the lack of BK polyomavirus staining in the biopsy and

nosuppression.3–6 The standard treatment for IgG4-RD is steroids;

lack of detectable BK by blood and urine PCR excludes a diagnosis

if patients do not respond or have a contraindication to steroids,

of BK-TIN. Immunophenotypic characterization, including an abun-

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rituximab is an alternative. Despite the brisk response to immu-

dance of CD4-positive T cells, scant PAX 8 and PAX 5 B- cells, and

nosuppression, IgG4-RD has a high relapse rate. In part due to the

lack of light chain restriction in plasma cells was not suggestive of a

treatment response of the disease, end-stage renal disease due to

PTLD.

IgG4-TIN is rare. However, inadequate treatment for IgG4-TIN may

The most challenging aspect of the biopsy was to differentiate

occur, particularly if it is not recognized as this specific type of in-

between recurrence of IgG4-TIN and PCRR. Plasma rich intersti-

terstitial nephritis as in the current case, or if clinicians are reluctant

tial infiltration is seen in approximately 3% to 14% of cases with

to treat patients with the extensive interstitial fibrosis that is often

acute rejection and commonly predicts a worse outcome for the

present in IgG4-TIN.

allograft.11,12 This uncommon variant of rejection has been defined

The differential diagnosis of a plasma cell–rich inflammatory

as plasma cell population of >10% of the infiltrating mononuclear

infiltrate in the allograft includes BK polyomavirus tubulointersti-

cells. PCRR typically occurs one or more years after transplantation.

tial nephritis (BK-TIN), posttransplant lymphoproliferative disorder

Although PCRR has been generally considered to be a subtype of T

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CHIBBAR et Al.

B

C

D

A

B

C

D

F I G U R E   2   Representative posttransplant kidney biopsy findings. 2A: Tubulointerstitial nephritis with abundant plasma cells associated with interstitial fibrosis (X400, Hematoxylin and eosin stain), 2B: Storiform fibrosis (bird’s-eye pattern fibrosis). Infiltrating lymphoplasmacytic cells are encircled by periodic-acid methenamine silver (PAM) positive thick fibers (×400); 2C: marked increase in IgG4-positive plasma cells by immunoperoxidase staining; 2D: electron microscopy showing electron dense deposits in the tubular basement membrane (×8000)

F I G U R E   3   Representative native kidney biopsy findings showing: 3A, 3B: Tubulointerstitial nephritis with storiform fibrosis and abundance of plasma cells (hematoxylin and eosin stain 100X and 400X); 3C: marked increase in IgG4-positive plasma cells by immunoperoxidase staining; 3D: electron microscopy showing electron dense deposits in tubular basement membrane

cell–mediated rejection (TCMR), cases of florid plasma cell infiltra-

PCH and 2 of 20 renal allograft biopsies with PCRR. They suggested

tion have been reported in association with late antibody-mediated

that IgG4+ PCH subgroup likely represents an overlap between allo

rejection (ABMR).13,14 Similar to our case, the infiltrated plasma cells

and auto immunity.15 A few studies have documented the associ-

in this variant of ABMR are mature and polyclonal, as verified by

ation between plasma cell rich interstitial inflammation in kidney

expression of both kappa and lambda light chains by immunohisto-

allograft and generation of DSA and C4d deposition in peritubular

chemistry. The IgG subtypes of plasma cells in PCRR is unknown. A

capillaries, which contribute to the poor allograft survival.16,17 In

recent study of plasma cell hepatitis (PCH) in liver allograft demon-

the current case, the histological features of IgG4-TIN with focal

strated >25 IgG4 positive plasma cells in 9 of 20 liver biopsies with

storiform fibrosis, increased IgG4-positive plasma cells, tubular

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CHIBBAR et Al.

basement membrane deposits as seen by immunofluoresce IgG antibody and electron microscopy, and the retrospective knowledge of IgG4-TIN as the native kidney disease supported a diagnosis of recurrent IgG4-TIN in our patient. In addition to recurrent IgG4-TIN, the transplant biopsy showed severe transplant glomerulopathy due to chronic active antibodymediated rejection. Patients who receive basiliximab induction are more likely to develop de novo DSA and antibody-mediated rejection18 and the patient may not have been adherent to the maintenance immunosuppressive therapy or under-immunosuppressed. Inadequate immunosuppression not only contributes to the development of de novo DSA, but it also could allow for the development of recurrent IgG4-TIN, which is known in the native kidney to have a high relapse rate upon discontinuation of immunosuppression. This patient lost his graft one year following the diagnosis of severe transplant glomerulopathy due to chronic active ABMR. Transplant glomerulopathy has a poor prognosis, particularly in the presence of high serum DSA levels and diffuse strong C4d staining indicative of microvascular inflammation.19 It would be reasonable to conclude, however, that the graft dysfunction and loss are largely due to transplant glomerulopathy. Several lessons can be learned from this case. First the underlying etiologies for tubulointerstitial nephritis such as IgG4-TIN should be considered whenever possible. Evaluation should include careful review of the clinical history for clues to systemic disease that may be associated with tubulointerstitial nephritis. There should be a low threshold to perform staining for IgG4 if classic feature of IgG4-TIN are present such as plasma cell–rich infiltrate and storiform fibrosis. Although IgG4-RD is thought of as a disease of middle-aged to older adults, IgG4-TIN may occur at a younger age as well, including in pediatric patients. Second, recurrence of interstitial nephritis after transplantation is commonly under-investigated as compared to recurrent glomerulonephritis, but recurrent interstitial nephritis should also be considered as a cause of renal graft dysfunction. Third, recurrent IgG4-TIN may be included in the differential diagnosis in transplant biopsies with plasma cell–rich interstitial infiltrate, if the cause of end stage kidney disease was interstitial nephritis of unknown etiology. Fourth, patients with IgG4-TIN should be closely followed-up for adherence and adequacy of immunosuppression.

D I S C LO S U R E The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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4. Zhang P, Cornell LD. IgG4-related tubulointerstitial nephritis. Adv Chronic Kidney Dis. 2017;24:94-100. 5. Chari ST. Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic’s HISORt criteria. J Gastroenterol. 2007;42(Suppl 18):39-41. 6. Saeki T, Nishi S, Imai N, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int. 2010;78:1016-1023. 7. Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4related disease. Arthritis Rheumatol. 2015;67:1688-1699. 8. Bracamonte E, Leca N, Smith KD, et al. Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy. Am J Transplant. 2007;6:1552-1560. 9. Choi J, Aubert O, Loupy A, et al. Assessment of tocilizumab (AntiInterleukin 6 Receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA sensitized renal allograft recipient. Am J Transplant. 2017;17(9):2381-2389. 10. Nishikawa K, Takeda A, Satoru M, et al. A case of IgG4-positive plasma cell-rich tubulointerstitial nephritis in a kidney allograft mimicking IgG4-related kidney disease. Nephrology. 2014;19(suppl 3):52-56. 11. Abbas K, Mubarak M, Zafar MN, et al. Plasma cell-rich acute rejections in living-related kidney transplantation: a clinicopathological study of 50 cases. Clin Transplant. 2015;29(9):835-841. 12. Gärtner V, Eigentler TK, Viebahn R. Plasma cell-rich rejection processes in renal transplantation: morphology and prognostic relevance. Transplantation. 2006;81:986-991. 13. Hasegawa J, Honda K, Wakai S, et al. Plasma cell-rich rejection after kidney transplantation and the role of donor-specific antibodies: a case report and review of the literature. Transplant Proc. 2015;47(8):2533-2536. 14. Rodrigues CA, Franco MF, Cristelli MP, Pestana JO, TedescoSilva H Jr. Clinicopathological characteristics ad effect of late acute rejection on renal transplant outcomes. Transplantation. 2014;98:885-892. 15. Castillo-Rama M, Sebagh M, Sasatomi E, et al. Plasma cell Hepatitis in liver allografts: identification and characterization of an IgG4 rich cohort. Am J Transpl. 2013;13:2966-2977. 16. Martin L, Charon-Barra C, Bocrie O, et al. Detection of plasma cells, C4d deposits and donor specific antibodies on sequential graft biopsies of renal transplant recipients with chronic dysfunction. Transpl Immunol. 2010;22:110-114. 17. Furuya M, Yamamoto I, Kobayashi A, et al. Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. Nephrology. 2014;19(Suppl 3):31-34. 18. Brokhof MM, Sollinger HW, Hager DR, et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients. Transplantation. 2014;97:612-617. 19. Issa N, Cosio FG, Gloor JM, et al. Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels. Transplantation. 2008;86:681-685.

How to cite this article: Chibbar R, Wright GR, Dokouhaki P, et al. Recurrent IgG4-related tubulointerstitial nephritis concurrent with chronic active antibody mediated rejection: A case report. Am J Transplant. 2018;00:1–5. https://doi.org/10.1111/ajt.14758

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