clinical investigation

http://www.kidney-international.org & 2013 International Society of Nephrology

The clinical course of patients with IgG4-related kidney disease Takako Saeki1, Mitsuhiro Kawano2, Ichiro Mizushima2, Motohisa Yamamoto3, Yoko Wada4, Hitoshi Nakashima5, Noriyuki Homma6, Yutaka Tsubata7, Hiroki Takahashi3, Tomoyuki Ito1, Hajime Yamazaki1, Takao Saito8 and Ichiei Narita4 1

Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan; 2Division of Rheumatology, Department of Internal Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan; 3First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; 4Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 5Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 6Department of Internal Medicine, Niigata Prefectural Shibata Hospital, Shibata, Niigata, Japan; 7Department of Internal Medicine, Niigata Prefectural Central Hospital, Joetsu, Niigata, Japan and 8 General Medical Research Center, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

Long-term follow-up for IgG4-related kidney disease, including relapse information, is sparse. To gather data on this we retrospectively examined the clinical course of 43 patients with IgG4-related kidney disease, in which most patients were treated with, and maintained on, corticosteroids. One month after the start of treatment, most of the abnormal serology and radiology parameters had improved. In 34 of the steroid-treated patients whose followup period was more than 12 months (median 34 months), excluding one hemodialysis patient, the estimated glomerular filtration rate (eGFR) before treatment was over 60 ml/min in 14 patients (group A) and under 60 ml/min in 20 patients (group B). In group A, there was no difference between the eGFR before therapy and at the last review. In group B, the mean eGFR before treatment (34.1 ml/min) was significantly improved after 1 month (45.0 ml/min), and renal function was maintained at a similar level through last follow-up. Among 24 evaluated patients at the last review, however, renal atrophy had developed in 2 of 9 in group A and in 9 of 15 in group B. Relapse of IgG4-related lesions occurred in 8 of 40 treated patients. Thus, the response of IgG4-related kidney disease to corticosteroids is rapid, not total, and the recovery of renal function persists for a relatively long time under low-dose maintenance. A largescale prospective study to formulate more useful treatment strategies is necessary. Kidney International (2013) 84, 826–833; doi:10.1038/ki.2013.191; published online 22 May 2013 KEYWORDS: chronic kidney disease; corticosteroid therapy; follow-up; IgG4-related disease; tubulointerstitial nephritis

Correspondence: Takako Saeki, Department of Internal Medicine, Nagaoka Red Cross Hospital, Senshu 2-297-1, Nagaoka, Niigata 940 2085, Japan. E-mail: [email protected] Received 19 September 2012; revised 13 February 2013; accepted 7 March 2013; published online 22 May 2013 826

IgG4-related disease (IgG4-RD) is a newly recognized fibroinflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4positive plasma cells, storiform fibrosis, and an elevated serum IgG4 concentration.1–4 The most common feature of the renal involvement in IgG4-RD is tubulointerstitial nephritis (TIN) with abundant IgG4-positive plasma cells, but glomerular lesions such as membranous glomerulonephritis have also been described.5–10 In addition, several radiologically evident lesions within the kidney, including the renal parenchyma and the renal pelvis, occur in association with other manifestations of IgG4-RD and often resolve with corticosteroid therapy. Therefore, the kidney lesion associated with IgG4-RD is referred to collectively as ‘IgG4-related kidney disease’ (IgG4-RKD), including radiologically identified renal lesions in the setting of some other form of organ involvement that has been confirmed histopathologically.7,11 Recent studies have revealed several characteristic clinical features of IgG4-related TIN (IgG4TIN), including predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, eosinophilia, characteristic radiologic findings in the kidney, and a good initial response to corticosteroids.5–10,12 However, longer follow-up data for IgG4-RKD, including relapse information, are still sparse. In this study, we retrospectively analyzed the longer-term clinical course of IgG4-RKD in detail in a larger cohort, including the responses to corticosteroid therapy. RESULTS Baseline characteristics

A total of 43 patients diagnosed as having definite IgG4-RKD according to the published diagnostic criteria7 were assessed in this study. The baseline clinicopathological characteristics Kidney International (2013) 84, 826–833

clinical investigation

T Saeki et al.: Clinical course of IgG4-RKD

of the patients are shown in Table 1. All of them were Japanese (33 men and 10 women) with an average age of 63.5±12.3 (27–83) years at the time of diagnosis of renal disease. The follow-up period after diagnosis was 3–189 months (mean 44.0±40.1), and 37 (86%) of the 43 patients were followed up for more than 12 months (Figure 1). Of the patients, 42 (97.7%) had accompanying IgG4-related extrarenal lesions. Computed tomography (CT) examinations were performed in all of the 43 patients, and these revealed characteristic renal features of IgG4-RKD7 in 31 (72.1%) of them (Table 1). The serum creatinine level was 0.4–7.26 mg/dl and the estimated glomerular filtration rate (eGFR) was 124.4–6.6 ml/min per 1.73 m2. Renal pathology data were available for 30 patients, and all of them were found to have characteristic IgG4-related TIN.7 Glomerular lesions other than global sclerosis were evident in 10 of the 30 patients: Henoch–Scho¨nlein purpura nephritis in two,13,14

membranous glomerulonephritis in two,10,15 focal and segmental endocapillary proliferative glomerulonephritis in two, mesangioproliferative glomerulonephritis (with mild IgG and IgA deposition in the glomeruli) in two, IgA nephropathy in one, and membranoproliferative glomerulonephritis in one patient. Four patients had a history of malignancy at the time of IgG4-RKD diagnosis (rectal cancer, breast cancer, urinary bladder cancer, and gastric cancer in one each, respectively). Treatment

Indications for treatment and the treatment regimen were decided according to the opinion of each attending physician. Among the 43 patients, 40 were treated with prednisolone (initial dose 20–60 mg/day; 0.35–1.0 mg/kg/day) for the lesions associated with IgG4-RD (Table 1 and Figure 1). The initial prednisolone dose had been reduced by B10% at

Table 1 | Baseline characteristics of 43 patients with IgG4-related kidney disease Sex

Follow-up (mo)

54 79 58 76 35 51 46 56 76 58 27 72 77 68 56 45 70 62

F M F F F F F M M F M M M M M M M M

35 32 32 36 83 66 33 27 72 (dead) 45 47 30 26 58 55 34 6 7

19 20 21 22 23

61 59 42 58 65

M M M M M

189 18 29 47 19

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

58 67 75 63 68 83 80 60 60 68 55 61 75 75 69 64 74

M F M M M M M M M M M F F M M M M

48 19 6 (dead) 13 66 51 3 (dead) 156 16 24 124 23 31 14 10 (dead) 132 6

41 42 43

76 78 69

M M M

39 55 (HD) 31

No.

Age

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Extrarenal lesions Sa, La Ly La, Lu Sa, Lu Sa, La, RF Sa, Pa Sa Sa, Pa, Lu Sa, Ly, Pa, Lu Sa, La, Ly, Ma Sa, La, Ly, Pa Ly Sa Sa, La, Ly Sa, La, Ly Sa, La, RF Pa Sa, La, Ly, Pa, Pro, Ao, Lu Sa, Ly, Pa, Thr Sa, Pa, Pro, RF Sa, La, Pa, Lu He, Neu Sa, Ly, Lu, Pro, RF, Ao Sa, Ly, Lu Ly, Lu Sa, Ly, Lu Sa, Pa, Lu, Ao Sa Pa Sa, Ly Sa, La Sa, Ly Sa, Pa Ly, Lu Sa, Ly, Lu Sa Pa Sa, La Sa, La, Ly, RF, Ao Sa Pa Sa, La, Pa, Ly, Lu, Pro

Renal radiology

Renal pathology

IgG4 (No105)

Low-C

Cr (mg/dl)

eGFR (ml/min)

A E D A, D D A A, B A A D A B (plain) D B (plain) A A E A

NA TIN þ endocap NA TIN TIN TIN NA NA TIN NA NA TIN þ HSPN NA NA TIN þ MGN NA TIN NA

785 409 606 769 191 744 751 2169 1030 2150 1200 1100 438 2940 1920 671 623 1920

() (þ) () () () () () (þ) (þ) () (þ) (þ) () (þ) (þ) (þ) (þ) (þ)

0.4 0.54 0.55 0.59 0.6 0.6 0.6 0.7 0.71 0.73 0.8 0.8 0.86 0.9 0.9 0.9 0.9 0.92

124.4 108.6 86.0 73.7 90.3 81.1 83.6 90.3 81.4 63.1 96.2 72.5 65.8 64.8 68.6 73.0 64.3 62.8

C A A A D

TIN TIN NA TIN NA

730a 734 948 1470 1330

(þ) () () () ()

1.09 1.1 1.1 1.15 1.18

E (plain) E A,B A E E (plain) E (plain) B E (plain) A A A B (plain) E (plain) E (plain) A E (plain)

TIN TIN TIN TIN TIN TIN þ MN TIN þ MPGN TIN þ MGN TIN TIN þ IgAGN TIN NA TIN þ HSPN TIN TIN TIN TIN

1204 738 587 408 670 924 660 305a 886 736 1780 152 486 890 1340 1360 1370

(þ) NA (þ) () (þ) (þ) (þ) (þ) () (þ) () () (þ) () (þ) () (þ)

E (plain) A B (plain)

TIN TIN þ MN TIN þ endocap

1800 1860 1120

() (þ) (þ)

U-Pr/U-B

PSL Tx (mg/day)

(  )/(  ) (  )/( þ ) (  )/( þ ) (  )/(  ) (  )/(  ) NA/NA (  )/(  ) (  )/(  ) (  )/(  ) (  )/(  ) (  )/(  ) (2 þ )/(2 þ ) (  )/(  ) NA/NA (2 þ )/(±) (  )/(  ) (±)/(  ) (3 þ )/( þ )

40 20 20 20 50 40 40 35 0 0 50 30 20 60 50 40 30 40

54.3 54.2 59.8 51.9 48.9

( þ )/( þ ) (  )/(  ) (  )/(  ) (  )/(  ) (±)/(  )

60 40 40 30 45

1.2 1.23 1.34 1.36 1.37 1.48 1. 6 1.75 1.82 1.9 2.1 2.22 2.25 2.34 2.36 2.9 4.65

49.6 34.2 40.8 42.2 41.0 35.5 33.0 32.5 31.1 28.6 27.3 18.4 17.1 22.2 22.5 18.4 10.5

( þ )/(  ) (±)/( þ ) ( þ )/(  ) ( þ )/(  ) (  )/(  ) (3 þ )/(3 þ ) (2 þ )/( þ ) ( þ )/(±) ( þ )/(  ) (  )/(  ) ( þ )/(  ) ( þ )/(  ) (2 þ )/(2 þ ) ( þ )/( þ ) (2 þ )/(±) NA / NA (2 þ )/(2 þ )

30 40 30 20 40 40 0 50 30 30 40 30 30 35 30 20 30

5.4 6.17 7.26

8.9 7.6 6.6

( þ )/( þ ) (3 þ )/( þ ) (2 þ )/(2 þ )

40 20 30

Abbreviations: A, multiple low-density lesions on enhanced computed tomography; Ao, periaortitis; B, diffuse kidney enlargement; C, hypovascular solitary mass in the kidney; Cr, serum creatinine (mg/dl); D, hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface; E, normal; endocap, endocapillary hypercellularity; He, hepatopathy; HSPN, Henoch–Schonlein purpura nephritis; F, female; IgAGN, IgA nephropathy; IgG4, serum IgG4 (mg/dl); La, dacryoadenitis; Low C, low titer of serum complement; Lu, lung lesion; Ly, lymphadenitis; M, male; Ma, mastitis; MGN, mesangial proliferative glomerulonephritis; MN, membranous glomerulonephritis; Mo, month; MPGN, membranoproliferative glomerulonephritis; NA, not available; Neu, perineuritis; Pa, type 1 autoimmune pancreatitis; Pro, prostatitis; PSL Tx, initial dose of prednisolone; RF, retroperitoneal fibrosis; Sa, sialadenitis; Thr, thrombocytopenia; TIN, tubulointerstitial nephritis; U-B, hematuria; U-Pr, proteinuria. a Value under steroid therapy.

Kidney International (2013) 84, 826–833

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clinical investigation

T Saeki et al.: Clinical course of IgG4-RKD

IgG4-RKD (n = 43)

Steroid Tx (+) (n = 40)

Steroid Tx (–) (n = 3)

GFR.60 before Tx f/u.12 month (n = 2)

GFR< 60 before Tx f/u