NEPHROLOGY - CASE REPORT

IgG4-related tubulointerstitial nephritis presentingwith psychiatric manifestations and skin lesions

Raja Ramachandran • Venkatesh Rajakumar • Amit Rawat •

Ritambhra Nada • Vivek Kumar • Manish Rathi • Harbir S. Kohli •

Vinay Sakhuja • Vivekanand Jha

Received: 15 March 2013 / Accepted: 8 April 2013

� Springer Science+Business Media Dordrecht 2013

Abstract We describe a 21-year male with mood

disorder on lithium therapy and psoriasis-like skin

lesions presenting with rapidly progressive renal

failure. The kidney biopsy showed acute tubulointer-

stitial nephritis with immunoglobulin G4-positive

plasma cell infiltration. He was started on oral steroids

with a provisional diagnosis of IgG4-related tubulo-

interstitial nephritis. All dermatological, psychiatric

and renal manifestations dramatically improved, and

he was taken off lithium. He had a relapse of his

psychiatric symptoms on stopping steroids, and they

again responded to steroids.

Keywords Tubulointerstitial nephritis � IgG4 �Psychiatric disorders � Psoriasis � Corticosteroids

Introduction

IgG4-related disease (IgG4-RD) is a newly recognized

syndrome of uncertain etiology characterized by

tumor-like swelling of involved organs, tissue infil-

tration with IgG4-positive plasma cells and ‘‘stori-

form’’ fibrosis [1]. It comprises of collection of

disorders that have specific pathologic, serologic and

clinical features. Considered a multisystem disorder,

IgG4-Rd has been described in association with

autoimmune pancreatitis, sclerosing cholangitis, Mi-

kulicz’s disease, retroperitoneal fibrosis, chronic scle-

rosing aortitis, periaortitis, tubulointerstitial nephritis

and membranous glomerulonephritis [1–3]. Central

nervous system involvement by IgG4-RD causes

hypophysitis and pachymeningitis [4]. However, psy-

chiatric manifestations are not reported with IgG4-

RD. We describe the first report of IgG4-RD present-

ing with bipolar mood disorder and later developing

psoriasis-like lesion and acute interstitial nephritis.

Case report

A 21-year-old man presented to our hospital with

rapidly progressive renal failure. He was well 3 years

ago, when he started developing mood swings, was

diagnosed to have bipolar mood disorder and started on

lithium carbonate. Despite the appropriate therapeutic

levels, the symptom control was suboptimal. Eight

months ago, he had developed multiple erythematous

R. Ramachandran � V. Rajakumar � V. Kumar �M. Rathi � H. S. Kohli � V. Sakhuja � V. Jha (&)

Department of Nephrology, Postgraduate Institute of

Medical Education and Research, Chandigarh 160012,

India

e-mail: vjha@pginephro.org

A. Rawat

Department of Paediatric Allergy and Immunology,

Postgraduate Institute of Medical Education and

Research, Chandigarh 160012, India

R. Nada

Department of Histopathology, Postgraduate Institute of

Medical Education and Research, Chandigarh 160012,

India

123

Int Urol Nephrol

DOI 10.1007/s11255-013-0447-6

plaques with sharply defined margins over extensor

aspect of elbows, knees, face and back (Fig. 1). A

diagnosis of plaque psoriasis was made at another

healthcare facility, and he was treated with topical

calcipotriene and betamethasone dipropionate. The

skin lesions persisted, however. Three weeks prior to

presentation, he started having progressive loss of

appetite, weakness and malaise and became unable to

perform routine work. He was seen at another facility,

found to have renal failure and referred to our hospital.

There was no history of arthralgia, oral ulcers or other

features suggestive of any connective tissue disorder.

There was no hematuria/pyuria. On examination, the

pulse was 88 beats/min, blood pressure 120/80 mm Hg

and respiratory rate 18/min. Erythematous skin lesions

with well-defined margins covered with silvery white

scales over present over face, back, extensor aspect of

both elbows and back. Cardiovascular, neurological,

abdominal and chest examinations were unremarkable.

Investigations revealed a serum creatinine of 4.7 mg/dl

and blood urea nitrogen 55 mg/dl. Urinalysis showed

2? albumin and full field of leukocytes. There were no

dysmorphic erythrocytes, and Hansel’s stain for

eosinophils was negative. Twenty-four hour urine

protein was 1.8 gm. The hemoglobin was 12 gm/dl,

platelet count 144,000/mm3 and leukocyte count

6,000/mm3. Liver functions (AST 19 U/l, ALT 13

U/l, total bilirubin 0.4 mg/dl, ALP 90 U/l) were

normal. The serum albumin was 3.3 gm/dl and globulin

6.3 gm/dl. Serum and urine protein electrophoresis did

not reveal any monoclonal proteins. He tested negative

for HBsAg, anti HCV antibody and HIV-I/II, ANA and

ds-DNA. The complement levels (C3 and C4) were

within normal range. Ultrasound of genitourinary

system revealed normal sized kidneys. A kidney

biopsy was performed.

Light microscopy showed 10 glomeruli with dif-

fuse expansile interstitial infiltrate composed of lym-

phoplasmacytic cells along with few eosinophils

(Fig. 2). There was no accompanying fibrosis. Serial

sections did not reveal any vasculitis. Direct immu-

nofluorescence did not show deposition of immuno-

globulins or complements in the glomeruli or tubules.

Electron microscopic examination revealed no

immune deposits. Immunostain revealed large number

of plasma cells within interstitial infiltrate that stained

for IgG4 (Fig. 3). Overall features were suggestive of

IgG4-related tubulointerstitial nephritis. Skin biopsy

could not be done as the patient refused consent.

The serum IgG4 levels were 627 mg/dl (normal

47–150 mg/dl). A computerized tomography scan of

the abdomen, chest and magnetic resonance imaging

of the brain did not reveal any mass lesion. Thyroid

function tests (serum TSH 2.2 mIU/l) and serum

vitamin B12 levels (600 pg/ml) were normal. He was

started on oral prednisolone at 1 mg/kg/d. Within

3 weeks of starting steroids, the serum creatinine and

BUN decreased to 0.8 mg/dl and 10 mg/dl, respec-

tively, and urinalysis showed disappearance of pro-

teinuria and pyuria after 2 weeks. Interestingly, his

psychiatric and skin manifestations responded com-

pletely to steroids, and his lithium was stopped.

Steroids were tapered after 1 month and stopped over

the next 6 weeks. At this time, the serum IgG4 levels

had declined to 60 mg/dl. Within 2 weeks of stopping

steroids, he had a relapse of his psychiatric symptoms,

Fig. 1 Erythematous skin lesion with well-defined margin

covered with silver white scales over the backFig. 2 Photomicrograph shows expansile plasma cell-rich

infiltrate in the interstitium. (H&E, 940)

Int Urol Nephrol

123

and the serum IgG4 levels had climbed back to

350 mg/dl. In view of the previous dramatic response

to steroids, he was again started on steroids at 1 mg/kg

and the psychiatric symptoms again responded

promptly. This time, steroids were tapered to a

maintenance dose of 10 mg/day over a period of

3 weeks and continued thereafter. Currently, the

patient is on 10 mg/day of prednisolone and remains

in complete remission including psychiatric and

dermatological manifestations without any antipsy-

chotic therapy for the last 15 months.

Discussion

IgG4-RD affects a number of organs, viz. pancreas,

bile duct, lacrimal glands, salivary glands, central

nervous system, thyroid, lungs, liver, gastrointestinal

tract, kidney, prostate, retroperitoneum, arteries,

lymph nodes, skin and breast resulting in a wide

variety of diseases, including Mikulicz’s disease

(MD), autoimmune pancreatitis (AIP) [1, 3], hypoph-

ysitis, Riedel’s thyroiditis [4], lymphadenopathy,

retroperitoneal fibrosis, interstitial pneumonitis [5],

interstitial nephritis [6], prostatitis, inflammatory

aortic aneurysm and inflammatory pseudotumor.

In addition to the renal involvement, this case

presented with psychiatric and dermatological mani-

festations, which in fact antedated the renal presenta-

tion by years. The diagnosis was made on kidney

biopsy and elevated levels of serum IgG4 [1].

However, we could establish the link between the

other manifestations and the IgG4-RD only retrospec-

tively when they improved with steroid therapy,

allowing withdrawal of the specific therapy for these

conditions, relapsed when steroids were withdrawn

and again remitted on reinstitution of steroids. There

was a parallel change in the serum IgG4 levels, which

lends further support to the causality.

Renal involvement is seen in 15 % of IgG4-RD [6]

with tubulointerstitial nephritis (TIN), fibrosis and

abundant IgG4-positive plasma cell infiltration being

the characteristic histopathological features [7, 8].

Hydronephrosis associated with retroperitoneal fibro-

sis and tumors of the renal pelvis and urethra have also

been described. In contrast to other types of interstitial

nephritis, IgG4-related TIN is often associated with

extrarenal lesions, such as pancreatitis, sialadenitis

and lymphadenitis, and a high incidence of hypocom-

plementemia. Notably, the complement levels were

normal in this case.

Although many studies have found no significant

changes in the glomeruli, others have reported an

association with glomerular lesions, including mem-

branous nephropathy [6]. A definitive diagnosis of

IgG4-RD can be made in patients with the following

features (a) organ enlargement, mass or nodular

lesions or organ dysfunction; (b) serum IgG4 concen-

tration[135 mg/dl; and (c) histopathological findings

of [10 IgG4 cells/HPF and IgG4?/IgG? cell ratio

[40 % [1]. Our patient had all these three criteria,

thereby enabling us to make a definitive diagnosis of

IgG4-RD with IgG4-related TIN. The other possibility

initially considered was a lithium-induced chronic

interstitial nephritis but the absence of features to

suggest chronicity, complete reversal of renal func-

tions with steroid therapy and the presence of clumps

of IgG4? plasma cells on histology ruled out this

possibility.

Cutaneous manifestations of IgG4-RD have been

described. The chief findings include an erythematous

or flesh-colored papules or plaques over the face or

head including the scalp [7]. Histology shows subcu-

taneous lympho-plasmacytic infiltrate with some fol-

licle formation, abundant IgG4 plasma cells and

stromal fibrosis, mimicking descriptions of cutaneous

pseudolymphoma [9, 10]. Neurological manifesta-

tions of IgG4-RD take the form of hypophysitis and

pachymeningitis [4]. More than 20 cases of hypoph-

ysitis have been reported with varying degrees of

anterior and/or posterior hypopituitarism [11].

Fig. 3 Photomicrograph shows strong staining for IgG4 in

plasma cells in the interstitium. (Immunohistochemistry, 940)

Int Urol Nephrol

123

Psychiatric manifestations, however, have not been

reported with IgG4-RD, making our case to be the first

case with such a presentation. We propose this to be

possibly related to IgG4-RD, as there was a complete

response to steroids and a relapse of symptoms on

withdrawing steroids. Moreover, he could also be

taken off lithium. However, the exact mechanism of

psychiatric manifestations is not clear at the moment,

and further research is needed to throw some light.

In conclusion, this is the first report of IgG4-RD

presenting with psychiatric manifestations and der-

matological involvement and enlarges the clinical

spectrum of IgG4-RD.

Conflict of interest None.

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